WO2022218247A1

WO2022218247A1 - Deuterated compound as cdk4/6 inhibitor

Info

Publication number: WO2022218247A1
Application number: PCT/CN2022/086055
Authority: WO
Inventors: 尹磊; 姚郑林
Original assignee: 甘李药业股份有限公司
Priority date: 2021-04-12
Filing date: 2022-04-11
Publication date: 2022-10-20
Also published as: CN117222636A

Abstract

Provided are a deuterated compound as a CDK4/6 inhibitor, a preparation method therefor, a pharmaceutical composition comprising a deuterated compound, and a use thereof. Compared with a non-deuterated reference compound, the present invention has better metabolic stability and better pharmacokinetic properties, and is expected to reduce clinical dosage.

Description

作为CDK4/6抑制剂的氘代化合物Deuterated compounds as CDK4/6 inhibitors

技术领域technical field

本发明属于药物化学领域，具体涉及一种作为CDK4/6抑制剂的氘代化合物、其制备方法、含氘代化合物的药物组合物及其用途。The invention belongs to the field of medicinal chemistry, and in particular relates to a deuterated compound as a CDK4/6 inhibitor, a preparation method thereof, a pharmaceutical composition containing the deuterated compound and uses thereof.

背景技术Background technique

细胞周期蛋白依赖性蛋白激酶(Cyclin Dependent Kinase,CDK)是一类丝氨酸/苏氨酸激酶，作为细胞内重要的信号转导分子，和细胞周期蛋白(Cyclin)形成CDK-Cyclin复合物，参与细胞的生长、增殖、休眠或者进入凋亡。Cyclin Dependent Kinase (CDK) is a kind of serine/threonine kinase, which is an important signal transduction molecule in cells, and forms CDK-Cyclin complex with cyclin (Cyclin), which is involved in cellular growth, proliferation, dormancy or enter apoptosis.

目前CDK家族已经发现了13个成员，分别是CDK1-CDK13，其中CDK1、CDK2、CDK3、CDK4和CDK6与调节细胞增殖有关。Cyclin分为A-L，不同的CDK分别连接不同亚型的Cyclin。其中，Cyclin D家族(Cyclin D1，D2，D3)，在G1期开始表达，结合并激活CDK4和CDK6，形成CDK4/6-Cyclin D复合物，使包括视网膜母细胞瘤蛋白在内的一系列底物磷酸化。CDK4/6特异性的激活与一些肿瘤的增殖密切相关，因此开发CDK4/6抑制剂成为一种靶向***的有效手段。At present, 13 members of the CDK family have been found, namely CDK1-CDK13, among which CDK1, CDK2, CDK3, CDK4 and CDK6 are involved in regulating cell proliferation. Cyclin is divided into A-L, and different CDKs are connected to different subtypes of Cyclin. Among them, Cyclin D family (Cyclin D1, D2, D3) begins to express in G1 phase, binds and activates CDK4 and CDK6, forms CDK4/6-Cyclin D complex, makes a series of substrates including retinoblastoma protein phosphorylation. The specific activation of CDK4/6 is closely related to the proliferation of some tumors, so the development of CDK4/6 inhibitors has become an effective means of targeting tumors.

5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(以下简称“对照化合物1”)是一款高选择性的CDK4/6抑制剂。该药物的结构式为：5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methylpiperidine -4-yl)pyridin-2-yl)pyrimidin-2-amine (hereinafter referred to as "control compound 1") is a highly selective inhibitor of CDK4/6. The structural formula of the drug is:

其合成方法具体描述于WO2017/092635A1中。Its synthesis method is specifically described in WO2017/092635A1.

很多药物由于较差的吸收(absorption)、分布(distribution)、代谢(metabolism)及***(excretion)(ADME)性质从而限制了它们的在某些疾病上的使用，也是导致许多候选药物未能通过临床试验的原因。尽管采用特殊的制剂工艺或前药技术在某些情况下可以改善一些药物的ADME性质，但是对大多数候选药物存在的ADME问题仍不能有效解决，特别是针对药物的快速代谢问题，导致许多本来可以高效治疗疾病的药物由于过快的从体内代谢掉而难以成药。Many drugs have poor absorption, distribution, metabolism, and excretion (ADME) properties, which limit their use in certain diseases, and lead to many drug candidates failing to pass. Reasons for clinical trials. Although the ADME properties of some drugs can be improved in some cases by using special formulation technology or prodrug technology, the ADME problems of most candidate drugs cannot be effectively solved, especially for the rapid metabolism of drugs, which leads to many Drugs that can effectively treat diseases are difficult to become medicines because they are metabolized from the body too quickly.

因此，仍然需要具有CDK4/6抑制活性、且代谢稳定性更好、半衰期更长、药代动力学性质更好的化合物。Therefore, there is still a need for compounds with CDK4/6 inhibitory activity, better metabolic stability, longer half-life, and better pharmacokinetic properties.

发明内容SUMMARY OF THE INVENTION

本发明的目的在于提供一类具有CDK4/6抑制活性、药代动力学性质良好、毒副作用降低的化合物。The purpose of the present invention is to provide a class of compounds with CDK4/6 inhibitory activity, good pharmacokinetic properties and reduced toxic and side effects.

本发明第一方面提供了式(I)所示的化合物或其药学上可接受的盐：A first aspect of the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

其中，R ¹-R ²⁹分别是H或D，且R ¹-R ²⁹中至少一个是D；和 wherein R ¹ -R ²⁹ are each H or D, and at least one of R ¹ -R ²⁹ is D; and

所述式(I)化合物不包括以下化合物：The compounds of formula (I) do not include the following compounds:

在一个实施方案中，其中R ¹-R ¹⁵、和R ¹⁷-R ²⁹中至少一个是D；优选地，R ¹-R ¹⁵、R ¹⁷、和R ¹⁹-R ²⁹中至少一个是D；优选地，R ¹-R ¹²、R ¹⁷、R ¹⁹-R ²⁹中至少一个是D；优选地，R ¹-R ³、R ⁸-R ⁹、R ¹⁷、R ²¹、R ²³、R ²⁷-R ²⁹中至少一个是D。 In one embodiment, wherein at least one of R ¹ -R ¹⁵ , and R ¹⁷ -R ²⁹ is D; preferably, at least one of R ¹ -R ¹⁵ , R ¹⁷ , and R ¹⁹ -R ²⁹ is D; preferably Preferably, at least one of R ¹ -R ¹² , R ¹⁷ , R ¹⁹ -R ²⁹ is D; preferably, R ¹ -R ³ , R ⁸ -R ⁹ , R ¹⁷ , R ²¹ , R ²³ , R ²⁷ -R At least one of the ²⁹ is a D.

在一个实施方案中，其中R ¹-R ³是D；和/或R ⁸和R ⁹是D；和/或R ¹³-R ¹⁵是D；和/或R ¹⁶是D；和/或R ¹⁷是D；和/或R ¹⁸是D；和/或R ²¹和R ²³是D；和/或R ²⁷-R ²⁹是D。 and/or ^R8 and ^R9 are D; and/or ^R13 ^- ^R15 are ^D ; and/or ^R16 is D; and/or ^R17 and/or R ¹⁸ is D; and/or R ²¹ and R ²³ are D; and/or R ²⁷ - R ²⁹ are D.

在一个实施方案中，其中R ¹-R ³是D；和/或R ⁸和R ⁹是D；和/或R ¹³-R ¹⁵是D；和/或R ¹⁷是D；和/或R ²¹和R ²³是D；和/或R ²⁷-R ²⁹是D。 and/or ^R8 and ^R9 are D; and/or ^R13 ^- ^R15 are ^D ; and/or ^R17 is D; and/or ^R21 and R ²³ is D; and/or R ²⁷ -R ²⁹ are D.

在一个实施方案中，其中R ¹-R ³是D；和/或R ⁸-R ⁹是D；和/或R ¹⁷是D；和/或R ²¹和R ²³是D；和/或R ²⁷-R ²⁹是D。 and/or ^R8 ^- ^R9 are D; and/or ^R17 is ^D ; and/or ^R21 and ^R23 are D; and/or ^R27 -R ²⁹ is D.

在一个实施方案中，其中R ¹⁶是H，或R ¹³-R ¹⁵是H，或R ¹⁸是H。 In one embodiment, wherein ^R16 is H, or ^R13 - ^R15 are H, or ^R18 is H.

在一个实施方案中，其中，当R ¹⁶是D时，R ¹-R ³是D，和R ¹³-R ¹⁵是D；和/或R ¹-R ³是D，R ⁸-R ⁹是D，和R ¹³-R ¹⁵是D；和/或R ²¹和R ²³是D；和/或R ²⁷-R ²⁹是D；和/或R ¹⁷是D和R ²⁷-R ²⁹是D；和/或R ²¹是D，R ²³是D，和R ²⁷-R ²⁹是D；和/或R ¹-R ³是D，R ²¹是D，R ²³是D，和R ²⁷-R ²⁹是D。 In one embodiment, wherein, when R ¹⁶ is D, R ¹ -R ³ are D, and R ¹³ -R ¹⁵ are D; and/or R ¹ -R ³ are D, and R ⁸ -R ⁹ are D , and R ¹³ -R ¹⁵ are D; and/or R ²¹ and R ²³ are D; and/or R ²⁷ -R ²⁹ are D; and/or R ¹⁷ is D and R ²⁷ -R ²⁹ is D; and/or or R ²¹ is D, R ²³ is D, and R ²⁷ -R ²⁹ are D; and/or R ¹ -R ³ are D, R ²¹ is D, R ²³ is D, and R ²⁷ -R ²⁹ are D.

在一个实施方案中，所述化合物具有式(II)所示结构：In one embodiment, the compound has the structure of formula (II):

其中R ¹、R ²、R ³中至少一个是D，R ¹³-R ¹⁵分别是H或D；优选地，R ¹、R ²、和R ³是D,R ¹³-R ¹⁵分别是H或D；更优选，R ¹、R ²、和R ³是D,R ¹³-R ¹⁵至少一个是D。 wherein at least one of R ¹ , R ² and R ³ is D, and R ¹³ -R ¹⁵ are respectively H or D; preferably, R ¹ , R ² , and R ³ are D, and R ¹³ -R ¹⁵ are respectively H or D; D; more preferably, R ¹ , R ² , and R ³ are D, and at least one of R ¹³ -R ¹⁵ is D.

在一个实施方案中，所述化合物具有式(III)所示结构：In one embodiment, the compound has the structure of formula (III):

其中，R ¹-R ³、R ⁸-R ⁹、R ¹³-R ¹⁵分别是H或D；优选地，R ¹-R ³是D、和/或R ⁸-R ⁹是D、和/或R ¹³-R ¹⁵是D；优选地，R ¹-R ³是D、和R ¹³-R ¹⁵是D；优选地，R ¹-R ³是D，R ⁸-R ⁹是D，和R ¹³-R ¹⁵是D。 Wherein, R ¹ -R ³ , R ⁸ -R ⁹ , R ¹³ -R ¹⁵ are respectively H or D; preferably, R ¹ -R ³ are D, and/or R ⁸ -R ⁹ are D, and/or R ¹³ -R ¹⁵ are D; preferably, R ¹ -R ³ are D, and R ¹³ -R ¹⁵ are D; preferably, R ¹ -R ³ are D, R ⁸ -R ⁹ are D, and R ¹³ -R ¹⁵ is D.

在一个实施方案中，所述化合物具有式(IV)所示结构：In one embodiment, the compound has the structure of formula (IV):

其中，R ¹-R ¹⁵中至少一个是D；优选，R ¹-R ³是D，和/或R ⁸-R ⁹是D。 wherein at least one of R ¹ -R ¹⁵ is D; preferably, R ¹ -R ³ are D, and/or R ⁸ -R ⁹ are D.

在一个实施方案中，所述化合物具有式(V)所示结构：In one embodiment, the compound has the structure of formula (V):

其中，R ¹-R ³、R ¹³-R ¹⁶分别是H或D；优选，R ¹-R ³是D，和/或R ¹³-R ¹⁵是D。 Wherein, R ¹ -R ³ , R ¹³ -R ¹⁶ are H or D respectively; preferably, R ¹ -R ³ are D, and/or R ¹³ -R ¹⁵ are D.

在一个实施方案中，所述化合物具有式(VI)所示结构：In one embodiment, the compound has the structure of formula (VI):

其中，R ¹-R ³、R ⁸、R ⁹、R ¹³-R ¹⁶分别是H或D；优选地，R ¹-R ³是D，和/或R ¹³-R ¹⁵是D，和/或R ⁸和R ⁹是D；优选地，R ¹⁶是D。 wherein, R ¹ -R ³ , R ⁸ , R ⁹ , R ¹³ -R ¹⁶ are H or D respectively; preferably, R ¹ -R ³ are D, and/or R ¹³ -R ¹⁵ are D, and/or ^R8 and ^R9 are D; preferably, ^R16 is D.

在一个实施方案中，所述化合物具有式(VII)所示结构：In one embodiment, the compound has the structure of formula (VII):

其中，R ¹-R ³、R ⁸、R ⁹、R ¹³-R ²⁶分别是H或D；优选地，R ¹-R ³是D；和/或R ⁸和R ⁹是D；和/或R ¹³-R ¹⁵是D；和/或R ¹⁶是D；和/或R ¹⁷是D；和/或R ²¹和R ²³是D。 wherein, R ¹ -R ³ , R ⁸ , R ⁹ , R ¹³ -R ²⁶ are H or D respectively; preferably, R ¹ -R ³ are D; and/or R ⁸ and R ⁹ are D; and/or and/or R ¹⁶ is D; and/or R ¹⁷ is D; and/or ^{R 21} ^and R ²³ ^are D.

作为优选的实施方案中，所述化合物选自：As a preferred embodiment, the compound is selected from:

如无特别说明，术语“本发明的化合物”，是指式(I)化合物及其盐,包括化合物的药学上可接受的盐以及所有立体异构体(包括但不限于非对映异构体和对映异构体)、互变异构体、同位素化合物、其前药、溶剂合物、和水合物。Unless otherwise specified, the term "compounds of the present invention" refers to compounds of formula (I) and salts thereof, including pharmaceutically acceptable salts of the compounds and all stereoisomers (including but not limited to diastereomers) and enantiomers), tautomers, isotopic compounds, prodrugs, solvates, and hydrates thereof.

术语“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。药学上可接受的盐的例子包括但不限于：(1)酸加成盐，和无机酸例如盐酸、硫酸、氢溴酸、硝酸、磷酸等形成的盐；或和有机酸例如苹果酸、富马酸、马来酸、苯甲酸、苯乙酸、琥珀酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、羟基乙酸、肉桂酸、丙酮酸、甲酸、乙酸、丙酸、草酸、丙二酸、丙烯酸、扁桃酸等形成的盐；或者(2)碱加成盐，和碱金属例如锂、钠、钾等形成的盐；和碱土金属例如钙、镁等形成的盐；和有机碱例如铵、胆碱、二乙醇胺、赖氨酸、乙二胺、叔丁胺、叔辛胺、三(羟甲基)氨基甲烷、N-甲基葡萄糖胺、三乙醇胺、脱氢松香胺等形成的盐。对于本领域的技术人员而言，其他的药学上可接受的盐是已知的。The term "pharmaceutically acceptable salts" refers to salts that retain the biological efficacy of the free acids and bases of a specified compound without biologically adverse effects. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, and salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; or with organic acids such as malic acid, rich Maleic acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid , acrylic acid, mandelic acid, etc.; or (2) base addition salts, and salts formed with alkali metals such as lithium, sodium, potassium, etc.; and alkaline earth metals such as calcium, magnesium, etc.; , choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, triethanolamine, dehydrorosin amine and other salts. Other pharmaceutically acceptable salts are known to those skilled in the art.

术语“同位素化合物”是指本发明的通式(I)化合物中含有一个或多个天然或非天然丰度的原子同位素。非天然丰度的原子同位素包括但不限于氘( ²H或D)、氚( ³H或T)、碘-125( ¹²⁵I)、磷-32( ³²P)、碳-13( ¹³C)或碳-14( ¹⁴C)。本发明中所合成的化合物的任何原子若没有特别指定，可代表该原子的任何一种稳定的同位素。除非特别说明，当结构中某一位置被定义为H即氢(H-1)时，该位置仅含天然存在的同位素量(0.015％)。 The term "isotopic compound" means that the compounds of general formula (I) of the present invention contain one or more atomic isotopes in natural or unnatural abundance. Atomic isotopes in unnatural abundance include, but are not limited to, deuterium ( ² H or D), tritium ( ³ H or T), iodine-125 ( ¹²⁵ I), phosphorus-32 ( ³² P), carbon-13 ( ¹³ C) or carbon-14 ( ¹⁴ C). Any atom of the compounds synthesized in the present invention, unless otherwise specified, may represent any stable isotope of that atom. Unless otherwise specified, when a position in a structure is defined as H, ie hydrogen (H-1), that position contains only the naturally occurring isotope amount (0.015%).

“氘”或“D”或“d”表示氢的同位素，其核含有一个质子和一个中子。当特别的位置被指定为含有氘时，应当理解的是该位置的氘的丰度大于氘的天然丰度(通常为0.015％)。除非另外说明，否则当某位置被特别指定为“D”或“氘”时，该位置应当理解为含有丰度大于氘的天然丰度的氘。"Deuterium" or "D" or "d" means an isotope of hydrogen whose nucleus contains one proton and one neutron. When a particular position is designated as containing deuterium, it is understood that the abundance of deuterium at that position is greater than the natural abundance of deuterium (typically 0.015%). Unless otherwise stated, when a position is specifically designated as "D" or "deuterium", that position is understood to contain deuterium in greater abundance than the natural abundance of deuterium.

本发明中所合成的化合物的氘代率是指合成的同位素含量与天然存在的同位素量的比值。本发明中所合成的化合物的每个指定氘原子的氘代率可至少为3333.3倍(50％)、至少为4000倍(60％)、至少为4500倍(67.5％)、至少为5000倍(75％)、至少为5333.3倍(80％)、至少为6000倍(90％)、至少为6333.3倍(95％)、至少为6466.7倍(97％)、至少为6566.7倍(98.5％)、至少为6600倍(99％)、至少为6633.3倍(99.5％)。The deuteration rate of a compound synthesized in the present invention refers to the ratio of the synthetic isotope content to the naturally occurring isotope content. The deuteration rate of each designated deuterium atom of the compounds synthesized in the present invention may be at least 3333.3 times (50%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times ( 75%), at least 5333.3 times (80%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times (99%), at least 6633.3 times (99.5%).

本发明中所合成的化合物中的某位置的氢同位素体的量取决许多因素，其中包括氘代试剂(如D ₂O、D ₂、NaBD ₄、LiAlD ₄等)的氘同位素纯度以及引入氘同位素合成方法的有效性。然而，如前所述这种某位置的氢同位素体的量总数将少于49.9％。本发明中所合成的化合物中的某位置的氢同位素体的量总数将少于47.5％、40％、32.5％、25％、17.5％、10％、5％、3％、1％或0.5％。 The amount of hydrogen isotope at a position in the compounds synthesized in the present invention depends on many factors, including the deuterium isotope purity of the deuterated reagent (eg, _D2O , D2, _NaBD4 , _LiAlD4 , etc. ₎ and the introduction of the deuterium isotope Efficiency of synthetic methods. However, the total amount of hydrogen isotopologues at such a location will be less than 49.9% as previously described. The total amount of hydrogen isotope at a position in the compounds synthesized in the present invention will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5% .

本文中，任何未指定为氘的各原子以其天然同位素丰度存在。Herein, any atom not designated as deuterium is present in its natural isotopic abundance.

术语“溶剂合物”是指通过与溶剂分子配位形成固态或液态的配合物的本专利发明的化合物的形式。此类形式的实例为水合物、醇合物等。The term "solvate" refers to a form of a compound of the present invention that forms a complex in a solid or liquid state by coordination with solvent molecules. Examples of such forms are hydrates, alcoholates, and the like.

术语“前药”是指在体内转化成母体药物的任何药剂。前药常常是有用的，因为，在某些情况下，他们比母体药物更易于给药。例如，通过口服给药，它们是可生物利用的，而母体药物却不是。前药相对于母体药物还可改善药物组合物中的溶解度。前药可经由酶的方法以及代谢水解的途径被转化为母体药物。The term "prodrug" refers to any agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, by oral administration, they are bioavailable, whereas the parent drug is not. Prodrugs can also improve solubility in pharmaceutical compositions relative to the parent drug. Prodrugs can be converted to the parent drug via enzymatic methods as well as metabolic hydrolysis routes.

本发明的另一个方面提供了一种药物组合物，其包含本发明化合物或其药学上可接受的盐，以及一种或多种药学上可接受的载体或赋形剂。Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

可通过多种途径给予本发明的药物组合物，这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如，透皮、皮肤、眼和粘膜包括鼻内、***和直肠递药)、肺(例如，通过吸入或吹入粉末或气雾剂，包括通过喷雾器；气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或脑室内给药。The pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area being treated. May be delivered topically (eg, transdermally, dermally, ocularly, and mucous membranes including intranasal, vaginal, and rectal), pulmonary (eg, by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), Oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intracerebroventricular administration.

可接受的载体或赋形剂的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、***胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素等。药物组合物还可含有：润滑剂例如滑石粉、硬脂酸镁和矿物油；湿润剂；乳化剂和悬浮剂；防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯；甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明的药物组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。Some examples of acceptable carriers or excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose Vegetarian, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose, etc. The pharmaceutical compositions may also contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweetening and flavoring agents agent. The pharmaceutical compositions of the present invention can be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to a patient by using methods known in the art.

可按单位剂型配制组合物，每一剂量含约5～1000mg，更通常约100～500mg活性成分。The compositions may be formulated in unit dosage form, each dosage containing about 5 to 1000 mg, more usually about 100 to 500 mg, of active ingredient.

本发明化合物是CDK4/6抑制剂，因此能够治疗其中潜在的病理学是(至少部分是)由CDK4/6介导的疾病。这类疾病包括癌症和其它疾病，其中存在细胞增殖、凋亡或分化的障碍。The compounds of the present invention are CDK4/6 inhibitors and are therefore capable of treating diseases in which the underlying pathology is (at least in part) mediated by CDK4/6. Such diseases include cancer and other diseases in which there is a disorder of cell proliferation, apoptosis or differentiation.

可以用本发明化合物治疗的癌症的实例包括但不限于癌，例如膀胱癌、乳癌、结肠癌(例如结肠直肠癌，例如结肠腺癌和结肠腺瘤)、肾癌、表皮癌、肝癌、肺癌(例如腺癌、小细胞肺癌和非小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌(例如外分泌胰腺癌)、胃癌、***、甲状腺癌、鼻癌、头颈癌、***癌和皮肤癌(例如鳞状细胞癌)。可以用本发明化合物治疗的癌症的其它实例包括淋巴样系的造血肿瘤(例如白血病、急性淋巴细胞白血病、套细胞淋巴瘤、慢性淋巴细胞白血病、B-细胞淋巴瘤(例如弥漫性大B细胞淋巴瘤)、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、多毛细胞淋巴瘤和伯基特淋巴瘤)；骨髓系的造血肿瘤，例如急性和慢性髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病。其它癌症包括甲状腺滤泡癌；间质来源的肿瘤，例如纤维肉瘤或横纹肌肉瘤(habdomyosarcoma)；中枢或周围神经***的肿瘤，例如星形细胞瘤、神经母细胞瘤、神经胶质瘤、脑胶质瘤或神经鞘瘤；黑素瘤；***瘤；畸胎癌；骨肉瘤；着色性干皮病；视网膜母细胞瘤；角化棘皮瘤(keratoctanthoma)；甲状腺滤泡癌；和卡波西肉瘤。Examples of cancers that can be treated with the compounds of the present invention include, but are not limited to, cancers such as bladder cancer, breast cancer, colon cancer (eg, colorectal cancer, such as colon adenocarcinoma and colon adenoma), kidney cancer, epidermal cancer, liver cancer, lung cancer ( such as adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), esophagus, gallbladder, ovary, pancreas (eg, exocrine pancreatic cancer), stomach, cervix, thyroid, nose, head and neck, prostate, and skin Cancer (eg squamous cell carcinoma). Other examples of cancers that can be treated with the compounds of the invention include hematopoietic tumors of the lymphoid lineage (eg, leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, B-cell lymphomas (eg, diffuse large B cell lymphoma). tumor), T-cell lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of the myeloid lineage, such as acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia. Other cancers include thyroid follicular carcinoma; tumors of mesenchymal origin, such as fibrosarcoma or rhabdomyosarcoma; tumors of the central or peripheral nervous system, such as astrocytoma, neuroblastoma, glioma, encephalomyeloma stromal tumor or schwannoma; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; retinoblastoma; keratoctanthoma; follicular thyroid carcinoma; Western sarcoma.

本发明的另一方面提供了一种治疗CDK4/6介导的障碍或疾病的方法，包括对患有所述细胞增殖障碍性疾病的患者通过口服或非口服途径给予有效量的本发明化合物或其药学上可接受的盐，或其药物组合物。Another aspect of the present invention provides a method of treating a CDK4/6 mediated disorder or disease, comprising administering to a patient suffering from said cell proliferative disorder an effective amount of a compound of the present invention or orally or parenterally A pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

本发明的另一方面提供了一种本发明化合物或其药学上可接受的盐，或其药物组合物在制备治疗CDK4/6介导的障碍或疾病的药物中的用途。Another aspect of the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of CDK4/6 mediated disorders or diseases.

本发明的另一方面提供了一种化合物或其药学上可接受的盐，其用于治疗CDK4/6介导的障碍或疾病。Another aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof for use in the treatment of a CDK4/6 mediated disorder or disease.

优选地，上述哺乳动物、包括人类由异常细胞增殖引起的障碍或病症是指哺乳动物或人的癌症，更优选的是指人的癌症，包括恶性实体瘤和恶性非实体瘤，具体包括但不限于乳腺癌、肺癌、***癌、白血病、脑癌、胶质瘤和胃癌；和/或所述细胞增殖障碍性疾病选自艾滋病、动脉粥样硬化和血管支架植入后再狭窄中的一种或多种。Preferably, the above-mentioned disorders or conditions caused by abnormal cell proliferation in mammals, including humans, refer to mammalian or human cancers, more preferably human cancers, including malignant solid tumors and malignant non-solid tumors, specifically including but not Limited to breast cancer, lung cancer, prostate cancer, leukemia, brain cancer, glioma and gastric cancer; and/or the cell proliferation disorder disease is selected from one of AIDS, atherosclerosis and restenosis after stent implantation or more.

本发明的又一方面提供了一种制备式(VII)化合物的方法，包括下述步骤：在酸存在的条件下，使式(VIII)化合物与氘代试剂反应得到式(VII)化合物Another aspect of the present invention provides a method for preparing the compound of formula (VII), comprising the steps of: reacting the compound of formula (VIII) with a deuterated reagent in the presence of an acid to obtain the compound of formula (VII)

其中，R ¹-R ³、R ⁸、R ⁹、R ¹³-R ²⁶分别是H或D。 wherein R ¹ -R ³ , R ⁸ , R ⁹ , R ¹³ -R ²⁶ are H or D, respectively.

优选地，所述酸选自氘代盐酸、盐酸、三氯化铁、三氯化铝、氯化锌、醋酸、醋酸酐、三氟乙酸、三氟乙酸酐、三氟甲烷磺酸、苯甲酸、对甲基苯甲酸、对硝基苯甲酸、对甲氧基苯甲酸、3，5-二硝基苯甲酸、二苯基磷酸、苯基次膦酸、磷酸、次磷酸、苯乙酸、苯丙酸、三甲基乙酸、苯磺酸、对甲苯磺酸、苦杏仁酸、和水杨酸中的至少一种；和/或所述氘代试剂选自d ₆-DMSO、d ₇-DMF、d ₆-丙酮、CD ₃OD、D ₂O、CD ₃CN、和C ₆D ₆中的至少一种；更优选地，所述酸为氘代盐酸，和/或所述氘代试剂为D ₂O。 Preferably, the acid is selected from deuterated hydrochloric acid, hydrochloric acid, ferric chloride, aluminum trichloride, zinc chloride, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, benzoic acid , p-toluic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 3,5-dinitrobenzoic acid, diphenylphosphoric acid, phenylphosphinic acid, phosphoric acid, hypophosphorous acid, phenylacetic acid, benzene At least one of propionic acid, trimethylacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, mandelic acid, and salicylic acid; and/or the deuterated reagent is selected from d ₆ -DMSO, d ₇ -DMF At least one of , d ₆ -acetone, CD ₃ OD, D ₂ O, CD ₃ CN, and C ₆ D ₆ ; more preferably, the acid is deuterated hydrochloric acid, and/or the deuterated reagent is D ₂ O.

优选地，上述方法中R ¹-R ³是D；和/或R ⁸和R ⁹是D；和/或R ¹³-R ¹⁵是D；和/或R ¹⁶是D；和/或R ¹⁷是D；和/或R ²¹和R ²³是D。 Preferably, in the above method, R ¹ -R ³ are D; and/or R ⁸ and R ⁹ are D; and/or R ¹³ -R ¹⁵ are D; and/or R ¹⁶ is D; and/or R ¹⁷ is D; and/or R ²¹ and R ²³ are D.

该制备方法仅对对照化合物1的3H-吲哚环上的甲基上的氢实现氘代，具有极强的选择性。This preparation method only deuterates the hydrogen on the methyl group on the 3H-indole ring of the control compound 1, and has extremely strong selectivity.

本发明的再一方面提供了一种式(IX)所示的化合物或其药学上可接受的盐，Another aspect of the present invention provides a compound of formula (IX) or a pharmaceutically acceptable salt thereof,

其中，R ¹⁸-R ²⁹分别是H或D；X为离去基团或氨基；优选的，X是卤素或氨基，更优选是氟、溴、氯或氨基。 Wherein, R ¹⁸ -R ²⁹ are H or D respectively; X is a leaving group or amino; preferably, X is halogen or amino, more preferably fluorine, bromine, chlorine or amino.

本发明的再一方面提供了一种制备式(I)化合物的方法，包括使式(IX)化合物转化为式(I)化合物：Yet another aspect of the present invention provides a process for the preparation of a compound of formula (I), comprising converting a compound of formula (IX) into a compound of formula (I):

其中：R ¹⁷为D；和R ¹-R ¹⁶和R ¹⁸-R ²⁹分别是H或D，优选，R ¹-R ³是D，和/或R ¹³-R ¹⁵是D，和/或R ¹⁶是D。 wherein: R ¹⁷ is D; and R ¹ -R ¹⁶ and R ¹⁸ -R ²⁹ are respectively H or D, preferably, R ¹ -R ³ are D, and/or R ¹³ -R ¹⁵ are D, and/or R ¹⁶ is D.

本发明的再一方面提供了一种制备式(IX)化合物的方法，包括下述步骤：在酸存在的条件下，使式(X)化合物或其盐与式(XI)化合物反应得到式(IX)化合物：Another aspect of the present invention provides a method for preparing a compound of formula (IX), comprising the steps of: reacting a compound of formula (X) or a salt thereof with a compound of formula (XI) in the presence of an acid to obtain a compound of formula ( IX) Compounds:

其中，R ¹⁸-R ²⁹分别是H或D，优选R ¹⁸-R ²⁹是氢；X为离去基团或氨基；优选的，X是卤素或氨基，更优选是氟、溴、氯或氨基；和/或式(X)化合物的盐选自盐酸盐、硫酸盐、甲磺酸盐和对甲苯磺酸盐，优选是盐酸盐。 Wherein, R ¹⁸ -R ²⁹ are H or D respectively, preferably R ¹⁸ -R ²⁹ are hydrogen; X is a leaving group or amino; preferably, X is halogen or amino, more preferably fluorine, bromine, chlorine or amino ; and/or the salt of the compound of formula (X) is selected from the group consisting of hydrochloride, sulfate, mesylate and p-toluenesulfonate, preferably the hydrochloride.

优选地，所述酸为有机酸、无机酸、或路易斯酸；优选所述酸为硫酸、盐酸、磷酸、甲磺酸、对甲苯磺酸、醋酸、ZnCl ₂、FeCl ₃、AlCl ₃或SnCl ₄；优选地，所述酸为硫酸。 Preferably, the acid is an organic acid, an inorganic acid, or a Lewis acid; preferably, the acid is sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, ZnCl ₂ , FeCl ₃ , AlCl ₃ or SnCl ₄ ; Preferably, the acid is sulfuric acid.

优选地，上述制备方法进一步包括下述步骤：Preferably, the above-mentioned preparation method further comprises the following steps:

(1)使

与氘代试剂反应得到

(1) make

Reaction with deuterated reagents to obtain

(2)使

转化为

(X)或其盐。 (2) make

transform into

(X) or a salt thereof.

优选地，所述步骤(1)在Ir(OMe)(cod) ₂存在下进行；所述氘代试剂选自d ₆-DMSO、d ₇-DMF、d ₆-丙酮、CD ₃OD、D ₂O、CD ₃CN、和C ₆D ₆中的至少一种；优选地，所述氘代试剂为D ₂O。 Preferably, the step (1) is carried out in the presence of Ir(OMe)(cod) ₂ ; the deuterated reagent is selected from d ₆ -DMSO, d ₇ -DMF, d ₆ -acetone, CD ₃ OD, D ₂ _At least one of O, _CD3CN , and _C6D6 ; preferably, the deuterated reagent is _D2O .

药物分子上某些位置的氢因为空间位阻等原因也不易被氘代，式(IX)化合物是合成式(I)化合物的重要中间体，本发明人用特定的方法合成了R ¹⁷为D的式(IX)化合物，并以式(IX)化合物作为中间体进一步合成终产物，达到了对对照化合物1特定位点的氢进行氘代的技术效果。 Hydrogen at certain positions on the drug molecule is also not easily deuterated due to steric hindrance and other reasons. The compound of formula (IX) is an important intermediate for synthesizing the compound of formula (I). The inventor has synthesized R ¹⁷ by a specific method. D The compound of formula (IX) is obtained, and the compound of formula (IX) is used as an intermediate to further synthesize the final product, so as to achieve the technical effect of deuterating the hydrogen at the specific site of the control compound 1.

本发明的有益效果：Beneficial effects of the present invention:

1)与对照化合物1相比，本发明的化合物对人脑胶质瘤U87MG细胞具有相当或更优的抑制活性。1) Compared with the control compound 1, the compounds of the present invention have comparable or better inhibitory activity on human glioma U87MG cells.

2)与对照化合物1相比，本发明的化合物在人肝微粒体中具有更佳的代谢稳定性和更优异的药代动力学性质，有望降低临床的使用剂量，从而降低治疗成本以让更多患者受益。2) Compared with the control compound 1, the compound of the present invention has better metabolic stability and more excellent pharmacokinetic properties in human liver microsomes, and is expected to reduce the clinical dose, thereby reducing the treatment cost to allow more Many patients benefit.

3)本发明还提供了对对照化合物1特定位置的氢实现氘代的方法，具有极强的选择性和特异性。3) The present invention also provides a method for deuterating the hydrogen at a specific position of the control compound 1, which has extremely strong selectivity and specificity.

缩略语：Abbreviations:

1atm:1个大气压1atm: 1 atmosphere

ADME:药物的吸收、分布、代谢、***ADME: Absorption, distribution, metabolism, and excretion of drugs

C-D:碳氘键C-D: carbon deuterium bond

C-H:碳氢键C-H: carbon hydrogen bond

CDK:细胞周期蛋白依赖性激酶CDK: cyclin-dependent kinase

CDCl ₃:氘代氯仿 CDCl ₃ : Deuterated chloroform

DAPI：4',6-二脒基-2-苯基吲哚DAPI: 4',6-diamidino-2-phenylindole

DMSO:二甲基亚砜DMSO: Dimethyl sulfoxide

DMSO-d ₆:氘代二甲基亚砜 DMSO-d ₆ : Deuterated dimethyl sulfoxide

DMF:N,N-二甲基甲酰胺DMF:N,N-Dimethylformamide

DCM:二氯甲烷DCM:dichloromethane

DCl:氘代盐酸DCl: deuterated hydrochloric acid

dtbpy:4,4’-二叔丁基-2，2’-联吡啶dtbpy: 4,4'-di-tert-butyl-2,2'-bipyridine

EA:乙酸乙酯EA: Ethyl acetate

FBS：胎牛血清FBS: Fetal Bovine Serum

Grubbs Cat ^1st:二(三环己基膦)亚苄基二氯化钌 Grubbs Cat ^1st : bis(tricyclohexylphosphine)benzylidene ruthenium dichloride

¹H-NMR:核磁共振氢谱 ¹ H-NMR: Proton NMR

HPLC：高压制备液相色谱HPLC: High Pressure Preparative Liquid Chromatography

Ir(OMe)(cod) ₂:甲氧基(环辛二烯)铱(I)二聚体 Ir(OMe)(cod) ₂ : Methoxy(cyclooctadiene)iridium(I) dimer

LiAlD ₄:氘代四氢锂铝 LiAlD ₄ : Deuterated lithium aluminum tetrahydrogen

MeOH:甲醇MeOH: methanol

MEM:最低必需培养基MEM: Minimum Essential Medium

NaBD ₄:氘代硼氢化钠 NaBD ₄ : Sodium deuterated borohydride

NEAA:非必需氨基酸NEAA: Non-Essential Amino Acids

NBS:N-溴代丁二酰亚胺NBS:N-Bromosuccinimide

Pd/C:钯碳Pd/C: Palladium on carbon

PE:石油醚PE: petroleum ether

PBS：磷酸盐缓冲液PBS: Phosphate Buffered Saline

Pd ₂(dba) ₃:三[二亚苄基丙酮]二钯 Pd ₂ (dba) ₃ : tris[dibenzylideneacetone]dipalladium

Pd(pph ₃) ₄:四(三苯基膦)钯 Pd(pph ₃ ) ₄ : tetrakis(triphenylphosphine)palladium

Pd(dppf)Cl ₂:[1,1’-双(二苯基膦基)二茂铁]二氯化钯 Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

SnCl ₂:二氯化锡 SnCl ₂ : tin dichloride

TLC:薄层层析色谱TLC: Thin Layer Chromatography

THF:四氢呋喃THF: Tetrahydrofuran

xant-phos:4,5-双二苯基膦-9，9-二甲基氧杂蒽xant-phos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene

具体实施方式Detailed ways

下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的化学原料、试剂等，如无特殊说明，均为市售购买产品。The experimental methods in the following examples are conventional methods unless otherwise specified. The chemical raw materials, reagents, etc. used in the following examples are all commercially available products unless otherwise specified.

实施例1 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基-[D ₃])-哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物1) Example 1 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methyl-[ _D3 ])-piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 1)

步骤1)6-硝基-3',6'-二氢-[3,4'-二吡啶]-1'(2'H)-羧基叔丁酯Step 1) 6-Nitro-3',6'-dihydro-[3,4'-dipyridine]-1'(2'H)-carboxy tert-butyl ester

向反应瓶中分批加入5-溴-2-硝基吡啶(20.0g,99.05mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧基硼酸-2-基)-5,6-二氢吡啶-1(2H)-羧基叔丁酯(33.44g,108.16mol)，1,4-二氧六环/水(200mL/20mL),碳酸钾(40.2g,291.3mmol),Pd(pph ₃) ₂Cl ₂(0.692g,0.985mmol)。在氮气保护下将该混合物加热至80℃反应12小时,冷却至室温，浓缩，柱层析分离(PE/EA＝1:1-DCM/MeOH＝20:1)得到标题产物19g为黄色固体。MS(ESI):306.1[M+H] ⁺。 5-Bromo-2-nitropyridine (20.0 g, 99.05 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxyboronic acid- 2-yl)-5,6-dihydropyridine-1(2H)-carboxy tert-butyl ester (33.44g, 108.16mol), 1,4-dioxane/water (200mL/20mL), potassium carbonate (40.2 _g , 291.3 mmol), Pd( _pph3 )2Cl2 (0.692 _g , 0.985 mmol). The mixture was heated to 80°C for 12 hours under nitrogen protection, cooled to room temperature, concentrated, and separated by column chromatography (PE/EA=1:1-DCM/MeOH=20:1) to obtain 19 g of the title product as a yellow solid. MS(ESI): 306.1 [M+H] ⁺ .

步骤2)4-(6-氨基吡啶-3-基)哌啶-1-羧基叔丁酯Step 2) 4-(6-Aminopyridin-3-yl)piperidine-1-carboxy tert-butyl ester

向反应瓶中加入6-硝基-3',6'-二氢-[3,4'-二吡啶]-1'(2'H)-羧基叔丁酯(1.0g,3.27mmol)，乙酸乙酯/甲醇(6mL/6mL),Pd/C(0.2g)，通入氢气(1atm)，加热到50℃反应6小时，过滤，浓缩，得到标题产物802mg为类白色固体。MS(ESI):278.2[M+H] ⁺。 To the reaction flask was added 6-nitro-3',6'-dihydro-[3,4'-dipyridine]-1'(2'H)-carboxy tert-butyl ester (1.0 g, 3.27 mmol), acetic acid Ethyl ester/methanol (6 mL/6 mL), Pd/C (0.2 g), passed hydrogen (1 atm), heated to 50 °C for 6 hours, filtered and concentrated to obtain 802 mg of the title product as an off-white solid. MS(ESI): 278.2 [M+H] ⁺ .

步骤3)5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-胺 Step 3) 5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-amine

将4-(6-氨基吡啶-3-基)哌啶-1-羧基叔丁酯(700.0mg,2.53mmol)溶解在四氢呋喃(14mL)中,在低温下缓慢加入氘代氢化锂铝(253.4mg,6.03mmol)。然后加热升温到70℃反应3小时。反应毕，加入冰块淬灭反应，萃取，浓缩，柱层析分离(DCM/MeOH＝20:1-10:1)得到标题化合物459mg为灰白色固体。MS(ESI):195.3[M+H] ⁺。 4-(6-Aminopyridin-3-yl)piperidine-1-carboxy tert-butyl ester (700.0 mg, 2.53 mmol) was dissolved in tetrahydrofuran (14 mL), and lithium aluminum deuterium hydride (253.4 mg) was slowly added at low temperature , 6.03 mmol). Then, the temperature was heated to 70° C. to react for 3 hours. After the reaction was completed, ice cubes were added to quench the reaction, extracted, concentrated, and separated by column chromatography (DCM/MeOH=20:1-10:1) to obtain 459 mg of the title compound as an off-white solid. MS(ESI): 195.3 [M+H] ⁺ .

步骤4)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基-[D ₃])-哌啶-4-基)吡啶-2-基)嘧啶-2-胺 Step 4) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methyl-[ _D3 ])-piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚](150.0mg,0.449mmol)，5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-胺(78.4mg,0.404mmol)，醋酸钯(10.05mg,0.0448mmol),xant-phos(25.95mg,0.0448mmol)以及碳酸钾(185.9mg,1.347mmol)溶解在甲苯(10mL)和水(2mL)中，然后通氮气，加热到100℃反应2小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物90mg为白色固体。MS(ESI):492.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.45(d,J＝3.6Hz,2H),8.35(d,J＝8.6Hz,1H),8.29-8.22(m,1H),7.97(s,1H),7.90(d,J＝11.0Hz,1H),7.62(d,J＝8.7Hz,1H),3.21-3.20(d,J＝11.4Hz,2H),2.65-2.53(m，1H),2.40(s,3H),2.37-2.26(m，2H),2.23-1.97(m，8H),1.96-1.87(m,4H)。 5'-(2-chloro-5-fluoropyrimidin-4yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] (150.0 mg , 0.449mmol), 5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-amine (78.4mg, 0.404mmol), palladium acetate (10.05mg, 0.0448mmol), xant -phos (25.95 mg, 0.0448 mmol) and potassium carbonate (185.9 mg, 1.347 mmol) were dissolved in toluene (10 mL) and water (2 mL), and then heated to 100° C. for 2 hours under nitrogen flow. After the reaction was completed, the reaction solution was concentrated, extracted, passed through celite, separated, concentrated, and then separated by TLC and purified by HPLC, and lyophilized to obtain 90 mg of the title compound as a white solid. MS(ESI): 492.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.45(d, J=3.6Hz, 2H), 8.35(d, J=8.6Hz, 1H), 8.29-8.22(m, 1H), 7.97(s, 1H) ),7.90(d,J＝11.0Hz,1H),7.62(d,J＝8.7Hz,1H),3.21-3.20(d,J＝11.4Hz,2H),2.65-2.53(m,1H),2.40 (s, 3H), 2.37-2.26 (m, 2H), 2.23-1.97 (m, 8H), 1.96-1.87 (m, 4H).

实施例2 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物5)Example 2 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 5)

步骤1)5-氟嘧啶-2,4(1H,3H)-酮-6-[D]Step 1) 5-Fluoropyrimidine-2,4(1H,3H)-one-6-[D]

向密封的铁罐中依次加入5-氟尿嘧啶(5.0g,38.4mmol)和重水(40mL)。然后加热到190℃反应3小时。反应毕，冷却到室温，过滤得到标题化合物4g为黄色固体。MS(ESI):130.2[M-H] ⁺。 To the sealed iron jar was added 5-fluorouracil (5.0 g, 38.4 mmol) followed by deuterium (40 mL). Then it was heated to 190°C for 3 hours. After the reaction was completed, it was cooled to room temperature and filtered to obtain 4 g of the title compound as a yellow solid. MS(ESI): 130.2 [MH] ⁺ .

步骤2)2,4-二氯-5-氟嘧啶-6-[D]Step 2) 2,4-Dichloro-5-fluoropyrimidine-6-[D]

向反应瓶中依次加入5-氟嘧啶-2,4(1H,3H)-酮-6-[D](2.0g,15mmol),N,N-二异丙基乙胺(0.96g,7.9mmol)和三氯氧磷(7mL)。然后加热到110℃反应2小时。反应毕，将溶剂旋干，向反应瓶中加入冰块，然后萃取，分离，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物1.3g为淡黄色油状物。MS(ESI):168.1[M+H] ⁺。 5-Fluoropyrimidine-2,4(1H,3H)-one-6-[D] (2.0g, 15mmol), N,N-diisopropylethylamine (0.96g, 7.9mmol) were successively added to the reaction flask ) and phosphorus oxychloride (7 mL). Then it was heated to 110°C for 2 hours. After the reaction was completed, the solvent was spin-dried, ice cubes were added to the reaction flask, followed by extraction, separation, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography to obtain 1.3 g of the title compound as a pale yellow oil. MS(ESI): 168.1 [M+H] ⁺ .

步骤3)5'-(2-氯-5-氟嘧啶-4-基-6-[D])-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]Step 3) 5'-(2-Chloro-5-fluoropyrimidin-4-yl-6-[D])-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole ]

在氮气保护下，向反应瓶中加入异丙醇(15mL)、5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚](1.2g,4.25mmol)、醋酸钾(0.5g，5.1mmol)和双联频哪醇硼酸酯(1.2g，4.67mmol)，搅拌，加入1,1’-二(二苯基膦基)二茂铁二氯化钯(0.34g,0.425mmol)。升温至85±5℃保温反应12小时。反应液减压浓缩，然后加入纯化水和乙酸乙酯萃取，分液，水相废弃。将得到的有机相过滤并减压浓缩，得到中间体。将中间体和甲苯(20mL)转入反应瓶中，搅拌，然后加入2,4-二氯-5-氟嘧啶-6-[D](1.2g,3.6mmol)和磷酸钾(1.94g,7.2mmol)，搅拌，向反应瓶中加入1,1’-二(二苯磷基)二茂铁二氯化钯(0.26g,0.36mmol)，然后再加入纯化水(6mL)，升温至85±5℃并保温反应3小时。反应毕，浓缩，萃取，分离，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物为1.0g为淡黄色油状物。MS(ESI):335.3[M+H] ⁺。 Under nitrogen protection, isopropanol (15 mL), 5'-bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] (1.2 g, 4.25 mmol), potassium acetate (0.5 g, 5.1 mmol) and bispinacol borate (1.2 g, 4.67 mmol), stir, add 1,1'-bis(diphenylphosphino)ferrocene Palladium chloride (0.34 g, 0.425 mmol). The temperature was raised to 85±5°C and the reaction was incubated for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the liquids were separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to yield the intermediate. The intermediate and toluene (20 mL) were transferred into a reaction flask, stirred, and then 2,4-dichloro-5-fluoropyrimidine-6-[D] (1.2 g, 3.6 mmol) and potassium phosphate (1.94 g, 7.2 mmol) were added mmol), stir, add 1,1'-bis(diphenylphosphoryl)ferrocene palladium dichloride (0.26g, 0.36mmol) to the reaction flask, then add purified water (6mL), heat up to 85± The reaction was incubated at 5°C for 3 hours. After the reaction was completed, concentrated, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 1.0 g of the title compound as a pale yellow oil. MS(ESI): 335.3 [M+H] ⁺ .

步骤4)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺Step 4) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4-基-6-[D])-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚](112mg,0.334mmol)，5-(1-甲基哌啶-4-基)吡啶-2-胺(64.8mg,0.334mmol)，醋酸钯(7.5mg,0.0334mmol),xant-phos(19.32mg,0.0334mmol)以及碳酸钾(138mg,1mmol)溶解在甲苯(10mL)和水(2mL)中，然后通氮气，加热到100℃反应2小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物10mg为白色固体。MS(ESI):490.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.35(d,J＝8.4Hz,1H),8.23-8.20(m,2H),7.98(s,1H),7.91(d,J＝10.8Hz,1H),7.62(d,J＝7.6Hz,1H),3.15-3.13(m,2H),2.56-2.55(m,1H),2.45(s,3H),2.40(s,3H),2.03-2.24(m，8H),1.91-1.76(m，6H)。 Add 5'-(2-chloro-5-fluoropyrimidin-4-yl-6-[D])-7'-fluoro-2'-methylspiro[cyclopentane-1,3' to the reaction flask in turn -indole] (112 mg, 0.334 mmol), 5-(1-methylpiperidin-4-yl)pyridin-2-amine (64.8 mg, 0.334 mmol), palladium acetate (7.5 mg, 0.0334 mmol), xant- phos (19.32 mg, 0.0334 mmol) and potassium carbonate (138 mg, 1 mmol) were dissolved in toluene (10 mL) and water (2 mL), then heated to 100° C. for 2 hours under nitrogen flow. After the reaction was completed, the reaction solution was concentrated, extracted, passed through celite, separated, concentrated, and then separated by TLC and purified by HPLC, and lyophilized to obtain 10 mg of the title compound as a white solid. MS(ESI): 490.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.35 (d, J=8.4Hz, 1H), 8.23-8.20 (m, 2H), 7.98 (s, 1H), 7.91 (d, J=10.8Hz, 1H) ), 7.62(d, J＝7.6Hz, 1H), 3.15-3.13(m, 2H), 2.56-2.55(m, 1H), 2.45(s, 3H), 2.40(s, 3H), 2.03-2.24( m, 8H), 1.91-1.76 (m, 6H).

实施例3 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-3,4-[D ₂])吡啶-2-基)嘧啶-2-胺(化合物13) Example 3 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -yl)pyrimidin-2-amine (Compound 13)

步骤1)4-(6-氨基吡啶-3-基)哌啶-1-羧基叔丁酯-3,4-[D ₂] Step 1) 4-(6-Aminopyridin-3-yl)piperidine-1-carboxy tert-butyl ester _- 3,4-[D2]

向反应瓶中加入6-硝基-3',6'-二氢-[3,4'-二吡啶]-1'(2'H)-羧基叔丁酯(200.0mg,0.66mmol)，氘代甲醇(5mL),Pd/C(20mg)，通入氘气(1atm)，加热到50℃反应12小时，过滤，浓缩，得到标题产物162mg为灰色固体。MS(ESI):280.3[M+H] ⁺。 To the reaction flask was added 6-nitro-3',6'-dihydro-[3,4'-dipyridine]-1'(2'H)-carboxy tert-butyl ester (200.0 mg, 0.66 mmol), deuterium Substitute methanol (5 mL), Pd/C (20 mg), pass deuterium gas (1 atm), heat to 50° C. for 12 hours, filter, and concentrate to obtain 162 mg of the title product as a gray solid. MS(ESI): 280.3 [M+H] ⁺ .

步骤2)5-(1-(甲基哌啶-4-基-3,4-[D ₂])吡啶-2-胺 Step 2) 5-(1-(methylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -amine

将4-(6-氨基吡啶-3-基)哌啶-1-羧基叔丁酯-3,4-[D ₂](280mg,1.00mmol)溶解在四氢呋喃(10mL)中,在低温下缓慢加入氢化锂铝(91.4mg,2.4mmol)。然后加热升温到70℃反应3小时。反应毕，加入冰块淬灭反应，萃取，浓缩，柱层析分离(DCM/MeOH＝20:1-10:1)得到标题化合物123mg为灰白色固体。MS(ESI):194.3[M+H] ⁺。 4-(6-Aminopyridin-3-yl)piperidine-1-carboxytert-butyl ester-3,4-[D ₂ ] (280 mg, 1.00 mmol) was dissolved in tetrahydrofuran (10 mL) and added slowly at low temperature Lithium aluminum hydride (91.4 mg, 2.4 mmol). Then, the temperature was heated to 70° C. to react for 3 hours. After the reaction was completed, ice cubes were added to quench the reaction, extracted, concentrated, and separated by column chromatography (DCM/MeOH=20:1-10:1) to obtain 123 mg of the title compound as an off-white solid. MS(ESI): 194.3 [M+H] ⁺ .

步骤3)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-3,4-[D ₂])吡啶-2-基)嘧啶-2-胺 Step 3) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -yl)pyrimidin-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚](100.0mg,0.299mmol)，5-(1-(甲基哌啶-4-基-3,4-[D ₂])吡啶-2-胺(50.5mg,0.26mmol)，醋酸钯(6.72mg,0.0299mmol),xant-phos(17.3mg,0.0299mmol)以及碳酸钾(129.8mg,0.897mmol)溶解在甲苯(4mL)和水(1mL)中，然后通氮气，加热到100℃反应2小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物75mg为白色固体。MS(ESI):491.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.64(brs,1H),8.46(d,J＝3.6Hz,1H),8.35(d,J＝8.8Hz,1H),8.27(d,J＝1.6Hz,1H),7.97(s,1H),7.90(d,J＝11.2Hz,1H),7.61(dd,J ¹＝8.8Hz,J ²＝1.6Hz,1H),3.06-3.03(m,2H),2.40(s,3H),2.38(s,3H),2.23-2.09(m,8H),1.90-1.86(m,5H)。 5'-(2-chloro-5-fluoropyrimidin-4yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] (100.0 mg , 0.299 mmol), 5-(1-(methylpiperidin-4-yl-3,4-[D ₂ ]) pyridin-2-amine (50.5 mg, 0.26 mmol), palladium acetate (6.72 mg, 0.0299 mmol) ), xant-phos (17.3mg, 0.0299mmol) and potassium carbonate (129.8mg, 0.897mmol) were dissolved in toluene (4mL) and water (1mL), then passed nitrogen, heated to 100 ℃ and reacted for 2 hours. After the reaction, The reaction solution was concentrated, extracted, passed through celite, separated, concentrated, and then separated by TLC and purified by HPLC, and lyophilized to obtain 75 mg of the title compound as a white solid. MS(ESI): 491.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.64 (brs, 1H), 8.46 (d, J=3.6Hz, 1H), 8.35 (d, J=8.8Hz, 1H), 8.27 (d, J=1.6Hz) ,1H),7.97(s,1H),7.90(d,J=11.2Hz,1H),7.61(dd,J1 ⁼ 8.8Hz,J2=1.6Hz,1H ⁾ ,3.06-3.03(m,2H) , 2.40(s, 3H), 2.38(s, 3H), 2.23-2.09(m, 8H), 1.90-1.86(m, 5H).

实施例4 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物20) Example 4 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 20)

步骤1)吡啶-[D ₄]-2-胺 Step 1) Pyridin-[D ₄ ]-2-amine

向密封的铁罐中依次加入2-氨基吡啶(3.0g,31.9mmol)，Pd/C(600mg)和重水(100mL)。然后通氢气鼓泡5分钟后，将铁封罐加热到210℃反应8小时。反应毕，向反应液中加入二氯甲烷和甲醇(50mL)过滤除去钯碳，将滤液浓缩得到标题化合物2.1g为灰色固体。MS(ESI):99.1[M+H] ⁺。 To the sealed iron jar was added 2-aminopyridine (3.0 g, 31.9 mmol), Pd/C (600 mg) and deuterium (100 mL) sequentially. Then, after bubbling with hydrogen for 5 minutes, the iron-sealed pot was heated to 210° C. to react for 8 hours. After the reaction was completed, dichloromethane and methanol (50 mL) were added to the reaction solution to remove palladium carbon by filtration, and the filtrate was concentrated to obtain 2.1 g of the title compound as a gray solid. MS(ESI): 99.1 [M+H] ⁺ .

步骤2)5-溴吡啶-3,4,6-[D ₃]-2-胺 Step 2) 5-Bromopyridin-3,4,6-[ _D3 ]-2-amine

将吡啶-[D ₄]-2-胺(200mg,2.02mmol)溶解在DMF(5mL)中,在10度左右向反应瓶中加入NBS(399mg,2.2mmol)。加毕，室温搅拌反应2小时。加水淬灭反应，萃取，分液，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物189mg为灰色固体。MS(ESI):176.2[M+H] ⁺。 _Pyridin- [D4]-2-amine (200 mg, 2.02 mmol) was dissolved in DMF (5 mL), and NBS (399 mg, 2.2 mmol) was added to the reaction flask at about 10 degrees. After the addition, the reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 189 mg of the title compound as a gray solid. MS(ESI): 176.2 [M+H] ⁺ .

步骤3)6-氨基-3',6'-二氢-[3,4'-二氢吡啶]-1'(2'H)-羧酸叔丁基酯-2,4,5-[D ₃] Step 3) 6-Amino-3',6'-dihydro-[3,4'-dihydropyridine]-1'(2'H)-carboxylate tert-butyl ester-2,4,5-[D ₃ ]

向反应瓶中分批加入5-溴吡啶-3,4,6-[D ₃]-2-胺(1.0g,5.68mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧基硼酸-2-基)-5,6-二氢吡啶-1(2H)-羧基叔丁酯(2.15g,6.95mol)，1,4-二氧六环/水(6mL/1mL),碳酸钾(2.175g,17.2mmol),Pd(pph ₃) ₄(0.65g,0.568mmol)。在氮气保护下微波100℃反应1小时,冷却至室温，萃取，浓缩，柱层析分离(PE/EA＝1:1-DCM/MeOH＝20:1)得到标题产物1.0g为灰白色固体。MS(ESI):279.3[M+H] ⁺。 5-Bromopyridin-3,4,6-[D ₃ ]-2-amine (1.0 g, 5.68 mmol), 4-(4,4,5,5-tetramethyl-1) were added in portions to the reaction flask ,3,2-Dioxyboronic acid-2-yl)-5,6-dihydropyridine-1(2H)-carboxy tert-butyl ester (2.15g, 6.95mol), 1,4-dioxane/water (6 mL/1 mL), potassium carbonate (2.175 g, 17.2 mmol), Pd(pph ₃ ) ₄ (0.65 g, 0.568 mmol). The reaction was microwaved at 100°C for 1 hour under nitrogen protection, cooled to room temperature, extracted, concentrated, and separated by column chromatography (PE/EA=1:1-DCM/MeOH=20:1) to obtain 1.0 g of the title product as an off-white solid. MS(ESI): 279.3 [M+H] ⁺ .

步骤4)5-(1-(甲基哌啶-4-基)吡啶-3,4,6-[D ₃]-2-胺 Step 4) 5-(1-(methylpiperidin-4-yl)pyridin-3,4,6-[ _D3 ]-2-amine

将6-氨基-3',6'-二氢-[3,4'-二氢吡啶]-1'(2'H)-羧酸叔丁基酯-2,4,5-[D ₃](800mg,2.85mmol)溶解在四氢呋喃(30mL)中,在低温下缓慢加入2.5M氢化锂铝的四氢呋喃溶液(2.86mL,7.14mmol)。然后加热升温到70℃反应4小时。反应毕，加入冰块淬灭反应，萃取，浓缩，柱层析分离(DCM/MeOH＝20:1-10:1)得到标题化合物603mg为灰色固体。MS(ESI):195.3[M+H] ⁺。 6-Amino-3',6'-dihydro-[3,4'-dihydropyridine]-1'(2'H)-carboxylate tert-butyl ester-2,4,5-[D ₃ ] (800 mg, 2.85 mmol) was dissolved in tetrahydrofuran (30 mL), and a 2.5M solution of lithium aluminum hydride in tetrahydrofuran (2.86 mL, 7.14 mmol) was slowly added at low temperature. Then, the temperature was heated to 70° C. to react for 4 hours. After the reaction was completed, ice cubes were added to quench the reaction, extracted, concentrated, and separated by column chromatography (DCM/MeOH=20:1-10:1) to obtain 603 mg of the title compound as a gray solid. MS(ESI): 195.3 [M+H] ⁺ .

步骤5)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺 Step 5) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚](257mg,0.769mmol)，5-(1-(甲基哌啶-4-基)吡啶-3,4,6-[D ₃]-2-胺(150mg,0.769mmol)，Pd ₂(dba) ₃(70mg,0.077mmol),xant-phos(88.9mg,0.154mmol)以及碳酸铯(750mg,2.3mmol)溶解在1，4-二氧六环(8mL)中，然后通氮气，微波加热到100℃反应1小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物94mg为白色固体。MS(ESI):492.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.00(s,1H),7.98(s,1H),7.61(dd,J ¹＝9.2Hz,J ²＝3.6Hz,1H),3.45-3.44(m,2H),2.69(s,3H),2.65-2.64(m,3H),2.40(s,3H),2.39-2.34(m,2H),2.19-1.86(m,10H)。 5'-(2-Chloro-5-fluoropyrimidin-4yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] (257mg, 0.769 mmol), 5-(1-(methylpiperidin-4-yl)pyridin-3,4,6-[ _D3 ]-2-amine (150 mg, 0.769 mmol), Pd2(dba ₎₃ ₍ 70 mg , 0.077 mmol), xant-phos (88.9 mg, 0.154 mmol) and cesium carbonate (750 mg, 2.3 mmol) were dissolved in 1,4-dioxane (8 mL), then nitrogen was passed through, and the microwave was heated to 100 ° C for reaction 1 After the reaction was completed, the reaction solution was concentrated, extracted, passed through diatomaceous earth, separated, continued to concentrate, separated by TLC and purified by HPLC, and lyophilized to obtain 94 mg of the title compound as a white solid. MS (ESI): 492.3 [M+ H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.61 (dd, J ¹ =9.2 Hz, J ² =3.6Hz, 1H), 3.45-3.44(m, 2H), 2.69(s, 3H), 2.65-2.64(m, 3H), 2.40(s, 3H), 2.39-2.34(m, 2H) ), 2.19-1.86 (m, 10H).

实施例5 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物21)Example 5 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-6'-[D])-nitrogen- (5-(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 21)

步骤1)4-溴-2-氟-3,6-双(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)胺Step 1) 4-Bromo-2-fluoro-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)amine

向反应瓶中依次加入4-溴-2-氟苯胺(10g,53mmol)、4,4,5,5-四甲基-1,3,2-二氧杂硼烷(40g,159mmol)、dtbpy(620mg,2.12mmol)、Ir(OMe)(cod) ₂(700mg,1.06mmol)，然后加入四氢呋喃(100mL)溶解后，通氮气然后加热到85℃反应12小时。反应毕，过滤，浓缩，萃取，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物3.1g为白色固体。MS(ESI):442.1[M+H] ⁺。 4-Bromo-2-fluoroaniline (10g, 53mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborane (40g, 159mmol), dtbpy were successively added to the reaction flask (620 mg, 2.12 mmol), Ir(OMe)(cod) ₂ (700 mg, 1.06 mmol), and then tetrahydrofuran (100 mL) was added to dissolve, and then heated to 85° C. with nitrogen to react for 12 hours. After completion of the reaction, filter, concentrate, extract, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain 3.1 g of the title compound as a white solid. MS(ESI): 442.1 [M+H] ⁺ .

步骤2)4-溴-2-氟苯-3，6-[D ₂]-胺 Step 2) 4-Bromo-2-fluorobenzene-3,6-[D ₂ ]-amine

向密封的铁罐中依次加入4-溴-2-氟-3,6-双(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)胺(5.34g,14.8mmol)、Ir(OMe)(cod) ₂(0.39g,0.6mmol)、重水(10mL)和四氢呋喃(40mL)。然后将反应液加热到145℃反应5小时。反应毕，冷却，乙酸乙酯萃取，浓缩，柱层析分离得到标题化合物2.85g为淡黄色油状物。MS(ESI):192.1[M+H] ⁺。 ¹H-NMR(400MHz,DMSO-d ₆)δ7.30(s,1H),5.30(brs,2H)。 Add 4-bromo-2-fluoro-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) sequentially to the sealed iron jar Amine (5.34 g, 14.8 mmol), Ir(OMe)(cod) ₂ (0.39 g, 0.6 mmol), deuterium (10 mL) and tetrahydrofuran (40 mL). The reaction solution was then heated to 145°C for 5 hours. After the reaction was completed, it was cooled, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain 2.85 g of the title compound as a pale yellow oil. MS(ESI): 192.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.30 (s, 1H), 5.30 (brs, 2H).

步骤3)(4-溴-2-氟苯-3,6-[D ₂])肼盐酸盐 Step 3) (4-Bromo- ₂ -fluorobenzene-3,6-[D2])hydrazine hydrochloride

将4-溴-2-氟苯-3，6-[D ₂]-胺(850mg,4.45mmol)溶解在8mL盐酸中，氮气保护，然后把反应液温度降低到-5℃，缓慢滴加亚硝酸钠(370mg,4.67mmol)溶解在4mL水。维持-5℃反应30分钟后，将反应液中缓慢滴加SnCl ₂(2.1g,8.9mmol)溶解在1mL HCl中。然后在0℃反应3小时。反应毕，过滤，萃取，浓缩，得到标题化合物936mg为白色固体。MS(ESI):192.1[M+H] ⁺。 Dissolve 4-bromo-2-fluorobenzene-3,6-[D ₂ ]-amine (850 mg, 4.45 mmol) in 8 mL of hydrochloric acid, under nitrogen protection, then reduce the temperature of the reaction solution to -5 °C, slowly add sub Sodium nitrate (370 mg, 4.67 mmol) was dissolved in 4 mL of water. After maintaining the reaction at -5°C for 30 minutes, SnCl ₂ (2.1 g, 8.9 mmol) was slowly added dropwise to the reaction solution and dissolved in 1 mL of HCl. It was then reacted at 0°C for 3 hours. After the reaction was completed, the mixture was filtered, extracted and concentrated to obtain 936 mg of the title compound as a white solid. MS(ESI): 192.1 [M+H] ⁺ .

步骤4)5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D]Step 4) 5'-Bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-6'-[D]

向反应瓶中依次加入(4-溴-2-氟苯-3,6-[D ₂])肼盐酸盐(936mg,3.89mmol)、环戊基乙酮(500mg,4.27mmol)和三乙胺(800mg,7.7mmol)以及15mL甲醇。然后保持在35℃反应3小时后，将反应液降温到-5℃后，缓慢滴加浓硫酸(1.6g,15.56mmol)。滴加完，35℃继续反应12小时。反应毕，用氨水调节 PH＝8，萃取，浓缩，柱层析分离得到标题化合物439mg为黄色油状物。MS(ESI):283.1[M+H] ⁺。 Into the reaction flask were sequentially added (4-bromo-2-fluorobenzene-3,6-[D ₂ ])hydrazine hydrochloride (936 mg, 3.89 mmol), cyclopentyl ethyl ketone (500 mg, 4.27 mmol) and triethyl acetate Amine (800 mg, 7.7 mmol) and 15 mL of methanol. Then, after keeping the reaction at 35°C for 3 hours, the reaction solution was cooled to -5°C, and then concentrated sulfuric acid (1.6 g, 15.56 mmol) was slowly added dropwise. After the dropwise addition, the reaction was continued at 35°C for 12 hours. After the reaction was completed, the pH was adjusted to 8 with ammonia water, extracted, concentrated, and separated by column chromatography to obtain 439 mg of the title compound as a yellow oil. MS(ESI): 283.1 [M+H] ⁺ .

步骤5)5'-(2-氯-5-氟嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-6'-[D]Step 5) 5'-(2-Chloro-5-fluoropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-6'-[ D]

在氮气保护下，向反应瓶中加入异丙醇(10mL)、5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D](239mg,0.84mmol)、醋酸钾(99.6mg，1mmol)和双联频哪醇硼酸酯(258mg，1mmol)，搅拌，加入1,1’-二(二苯膦基)二茂铁二氯化钯(61.9mg,0.084mmol)。升温至85±5℃保温反应12小时。反应液减压浓缩，然后加入纯化水和乙酸乙酯萃取，分液，水相废弃。将得到的有机相过滤并减压浓缩，得到中间体。将中间体和1,4-二氧六环(10mL)转入反应瓶中，搅拌，然后加入2,4-二氯-5-氟嘧啶(141.5mg,0.84mmol)和磷酸钾(449mg,2.1mmol)，搅拌，向反应瓶中加入四(三苯基膦)钯(89.8mg,0.07mmol)，然后再加入纯化水(3.3mL)，微波100℃反应1小时。反应毕，浓缩，萃取，分离，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物为163mg为黄色固体。MS(ESI):335.1[M+H] ⁺。 Under nitrogen protection, isopropanol (10 mL), 5'-bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'- Base-6'-[D] (239 mg, 0.84 mmol), potassium acetate (99.6 mg, 1 mmol) and bispinacol boronate (258 mg, 1 mmol), stir, add 1,1'-bis(diphenyl) phosphino)ferrocene palladium dichloride (61.9 mg, 0.084 mmol). The temperature was raised to 85±5°C and the reaction was incubated for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the liquids were separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to yield the intermediate. The intermediate and 1,4-dioxane (10 mL) were transferred to a reaction flask, stirred, and then 2,4-dichloro-5-fluoropyrimidine (141.5 mg, 0.84 mmol) and potassium phosphate (449 mg, 2.1 mmol) were added mmol), stirred, and tetrakis(triphenylphosphine)palladium (89.8 mg, 0.07 mmol) was added to the reaction flask, and then purified water (3.3 mL) was added, and the reaction was carried out at 100° C. in a microwave for 1 hour. After the reaction was completed, concentrated, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 163 mg of the title compound as a yellow solid. MS(ESI): 335.1 [M+H] ⁺ .

步骤6)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺Step 6) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-6'-[D])-nitrogen- (5-(1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-6'-[D](163mg,0.49mmol)，5-(1-(甲基哌啶-4-基)吡啶-2-胺(112mg,0.58mmol)，Pd ₂(dba) ₃(44.6mg,0.05mmol),xant-phos(56.4mg,0.1mmol)以及碳酸铯(476mg,1.47mmol)溶解在1，4-二氧六环(10mL)，然后通氮气，加热到100℃微波反应1小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物116mg为淡黄色固体。MS(ESI):490.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ 8.45(d,J＝3.6Hz,1H),8.35(s,1H),8.33(s,1H),8.24(d,J＝2.4Hz,1H),7.98(s,1H),7.62(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.16-3.13(m,2H),2.59-2.53(m,1H),2.45(s,3H),2.40(s,3H),2.27-2.08(m,8H),1.96-1.87(m,6H)。 Add 5'-(2-chloro-5-fluoropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-6 to the reaction flask '-[D] (163 mg, 0.49 mmol), 5-(1-(methylpiperidin-4-yl)pyridin-2-amine (112 mg, 0.58 mmol), Pd ₂ (dba) ₃ (44.6 mg, 0.05 mmol), xant-phos (56.4 mg, 0.1 mmol) and cesium carbonate (476 mg, 1.47 mmol) were dissolved in 1,4-dioxane (10 mL), and then heated to 100 °C with nitrogen for 1 hour microwave reaction. After completion, the reaction solution was concentrated, extracted, passed through diatomaceous earth, separated, concentrated, and then subjected to TLC separation and HPLC purification, and lyophilized to prepare 116 mg of the title compound as a pale yellow solid. MS(ESI): 490.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J=3.6 Hz, 1H), 8.35 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=2.4 Hz, 1H) ,7.98(s,1H),7.62(dd,J ¹ =8.8Hz,J ² =2.4Hz,1H),3.16-3.13(m,2H),2.59-2.53(m,1H),2.45(s,3H ), 2.40(s, 3H), 2.27-2.08(m, 8H), 1.96-1.87(m, 6H).

实施例6 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-4'-[D])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物25)Example 6 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-4'-[D])-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 25)

步骤1)(5-溴-2-氟苯基)氨基甲酸叔丁酯Step 1) tert-butyl (5-bromo-2-fluorophenyl)carbamate

向反应瓶中依次加入5-溴-2-氟苯胺(1.89g,10mmol)并且在水(10mL)中悬浮。加入二碳酸二叔丁酯(2.16g,12mmol)，导致加热和泡腾现象。将反应混合物进一步用水(50mL)稀释，然后在80℃加热反应8小时。在冷却至室温时，加入水(100mL)，并且将沉淀通过过滤收集并且用水充分洗涤。将固体残余物萃取至二氯甲烷(100mL)中，用硫酸镁干燥，过滤并且浓缩至干燥，得到标题化合物2.0g为浅黄色固体。MS(ESI):289.1[M+H] ⁺。 5-Bromo-2-fluoroaniline (1.89 g, 10 mmol) was sequentially added to the reaction flask and suspended in water (10 mL). Di-tert-butyl dicarbonate (2.16 g, 12 mmol) was added causing heating and effervescence. The reaction mixture was further diluted with water (50 mL) and then heated at 80°C for 8 hours. Upon cooling to room temperature, water (100 mL) was added, and the precipitate was collected by filtration and washed well with water. The solid residue was extracted into dichloromethane (100 mL), dried over magnesium sulfate, filtered and concentrated to dryness to give the title compound 2.0 g as a pale yellow solid. MS(ESI): 289.1 [M+H] ⁺ .

步骤2)(3-氨基-4-氟苯基)硼酸Step 2) (3-Amino-4-fluorophenyl)boronic acid

向反应瓶中依次加入(5-溴-2-氟苯基)氨基甲酸叔丁酯(2g,6.92mmol)、1，4-二氧六环(10mL)、双(频哪醇)二硼(2.74g,10.38mmol)和乙酸钾(1.36g,13.84mmol)。使氮气鼓泡通过混合物5分钟，再加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.56g，0.069mmol)，并且将反应混合物100℃加热反应12小时。在冷却时，将反应混合物在乙酸乙酯(80mL)和水(40mL)之间分配，将有机相用盐水(20mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残留物用10mL氯仿溶解，然后加入1mL三氟乙酸室温反应5小时。然后浓缩至干燥。将粗制残余物在氯仿(50mL)和水(50mL)之间分配，将水相用在氯仿(50mL)中的10％甲醇洗涤，通过加入碳酸氢钠将PH调节至7，并且用二氯甲烷洗涤。将水相浓缩至干燥，得到固体残余物，将其用二氯甲烷洗涤，溶解在甲醇中，过滤并且浓缩得到标题化合物1.18g为白色固体。MS(ESI):156.3[M+H] ⁺。 To the reaction flask were sequentially added (5-bromo-2-fluorophenyl) tert-butyl carbamate (2 g, 6.92 mmol), 1,4-dioxane (10 mL), bis(pinacol) diboron ( 2.74 g, 10.38 mmol) and potassium acetate (1.36 g, 13.84 mmol). Nitrogen was bubbled through the mixture for 5 minutes before [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (0.56 g, 0.069 mmol) was added, and The reaction mixture was heated at 100°C for 12 hours. Upon cooling, the reaction mixture was partitioned between ethyl acetate (80 mL) and water (40 mL), the organic phase was washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 10 mL of chloroform, and then 1 mL of trifluoroacetic acid was added to react at room temperature for 5 hours. It is then concentrated to dryness. The crude residue was partitioned between chloroform (50 mL) and water (50 mL), the aqueous phase was washed with 10% methanol in chloroform (50 mL), the pH was adjusted to 7 by addition of sodium bicarbonate, and dichloromethane was added. Methane wash. The aqueous phase was concentrated to dryness to give a solid residue which was washed with dichloromethane, dissolved in methanol, filtered and concentrated to give the title compound 1.18 g as a white solid. MS(ESI): 156.3 [M+H] ⁺ .

步骤3)2-氟苯-5-[D]-胺Step 3) 2-Fluorobenzene-5-[D]-amine

向密封的铁罐中依次加入(3-氨基-4-氟苯基)硼酸(1.18g,7.54mmol)、Ir(OMe)(cod) ₂(131mg,0.226mmol)、重水(5mL)和四氢呋喃(20mL)。然后将反应液加热到145℃反应5小时。反应毕，冷却，乙酸乙酯萃取，浓缩，柱层析分离得到标题化合物900mg为淡黄色油状物。MS(ESI):113.3[M+H] ⁺。 Into a sealed iron jar were sequentially added (3-amino-4-fluorophenyl)boronic acid (1.18 g, 7.54 mmol), Ir(OMe)(cod) ₂ (131 mg, 0.226 mmol), heavy water (5 mL) and tetrahydrofuran ( 20mL). The reaction solution was then heated to 145°C for 5 hours. After the reaction was completed, it was cooled, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain 900 mg of the title compound as a pale yellow oil. MS(ESI): 113.3 [M+H] ⁺ .

步骤4)4-溴-2-氟苯-5-[D]-胺Step 4) 4-Bromo-2-fluorobenzene-5-[D]-amine

将2-氟苯-5-[D]-胺(400mg,3.57mmol)溶解在THF(5mL)中,在10℃左右向反应瓶中加入NBS(690mg,3.89mmol)。加毕，室温搅拌反应5小时。加水淬灭反应，萃取，分液，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物438mg为白色固体。MS(ESI):191.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ7.17(d,J＝10.8Hz,1H),6.70(m,1H)，3.73(brs,2H)。 2-Fluorobenzene-5-[D]-amine (400 mg, 3.57 mmol) was dissolved in THF (5 mL), and NBS (690 mg, 3.89 mmol) was added to the reaction flask at about 10°C. After the addition, the reaction was stirred at room temperature for 5 hours. The reaction was quenched by adding water, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 438 mg of the title compound as a white solid. MS(ESI): 191.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.17 (d, J=10.8 Hz, 1H), 6.70 (m, 1H), 3.73 (brs, 2H).

步骤5)(4-溴-2-氟苯基-5-[D])肼盐酸盐Step 5) (4-Bromo-2-fluorophenyl-5-[D])hydrazine hydrochloride

将4-溴-2-氟苯-5-[D]-胺(950mg,5mmol)溶解在14mL盐酸中，氮气保护，然后把反应液温度降低到-5℃，缓慢滴加亚硝酸钠(2.26g,10mmol)溶解在7mL水。维持-5℃反应30分钟后，再反应液中缓慢滴加SnCl ₂.H ₂O(1.1g,6mmol)溶解在3mL HCl中。然后在0℃反应3小时。反应毕，过滤，萃取，浓缩，得到标题化合物730mg为黄色固体。MS(ESI):206.1[M+H] ⁺。 4-Bromo-2-fluorobenzene-5-[D]-amine (950 mg, 5 mmol) was dissolved in 14 mL of hydrochloric acid, under nitrogen protection, then the temperature of the reaction solution was lowered to -5 °C, and sodium nitrite (2.26 ℃) was slowly added dropwise. g, 10 mmol) was dissolved in 7 mL of water. After maintaining the reaction at -5°C for 30 minutes, SnCl ₂ .H ₂ O (1.1 g, 6 mmol) was slowly added dropwise to the reaction solution and dissolved in 3 mL of HCl. It was then reacted at 0°C for 3 hours. After completion of the reaction, filter, extract and concentrate to obtain 730 mg of the title compound as a yellow solid. MS(ESI): 206.1 [M+H] ⁺ .

步骤6)5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-4'-[D]Step 6) 5'-Bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-4'-[D]

向反应瓶中依次加入(4-溴-2-氟苯基-5-[D])肼盐酸盐(730mg,3.54mmol)、环戊基乙酮(383mg,3.54mmol)和三乙胺(716mg,7.07mmol)以及12mL甲醇。然后保持在35℃反应3小时后，将反应液降温到-5℃后，缓慢滴加浓硫酸(1.42g,14.5mmol)。滴加完，40℃继续反应12小时。反应毕，用氨水调节PH＝8，萃取，浓缩，柱层析分离得到标题化合物540mg为黄色油状物。MS(ESI):283.1[M+H] ⁺。 Into the reaction flask were sequentially added (4-bromo-2-fluorophenyl-5-[D])hydrazine hydrochloride (730 mg, 3.54 mmol), cyclopentyl ethyl ketone (383 mg, 3.54 mmol) and triethylamine ( 716 mg, 7.07 mmol) and 12 mL of methanol. Then, after keeping the reaction at 35°C for 3 hours, the reaction solution was cooled to -5°C, and then concentrated sulfuric acid (1.42 g, 14.5 mmol) was slowly added dropwise. After the dropwise addition, the reaction was continued at 40°C for 12 hours. After the reaction was completed, the pH was adjusted to 8 with ammonia water, extracted, concentrated, and separated by column chromatography to obtain 540 mg of the title compound as a yellow oil. MS(ESI): 283.1 [M+H] ⁺ .

步骤7)5'-(2-氯-5-氟嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-4'-[D]Step 7) 5'-(2-Chloro-5-fluoropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-4'-[ D]

在氮气保护下，向反应瓶中加入异丙醇(10mL)、5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-4'-[D](540mg,1.91mmol)、醋酸钾(225.2mg，2.30mmol)和双联频哪醇硼酸酯(730mg，2.87mmol)，搅拌，加入1,1’-二(二苯磷基)二茂铁二氯化钯(134mg,0.18mmol)。升温至85±5℃保温反应12小时。反应液减压浓缩，然后加入纯化水和乙酸乙酯萃取，分液，水相废弃。将得到的有机相过滤并减压浓缩，得到中间体。将中间体和1，4-二氧六环(8mL)转入反应瓶中，搅拌，然后加入2,4-二氯-5-氟嘧啶(281mg,1.67mmol)和磷酸钾(886.5mg,4.18mmol)，搅拌，向反应瓶中加入四(三苯基膦)钯(161mg,0.14mmol)，然后再加入纯化水(2mL)，微波100℃反应1小时。反应毕，浓缩，萃取，分离，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物为157mg为黄色固体。MS(ESI):335.1[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.55(d,J＝3.2Hz,1H),7.94(d,J＝10.4Hz,1H),2.44(s,3H),2.21-2.06(m,6H)，1.97-1.88(m,2H)。 Under nitrogen protection, isopropanol (10 mL), 5'-bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'- base-4'-[D] (540 mg, 1.91 mmol), potassium acetate (225.2 mg, 2.30 mmol) and bispinacol boronate (730 mg, 2.87 mmol), stirred, added 1,1'-bis( Diphenylphosphoryl)ferrocene palladium dichloride (134 mg, 0.18 mmol). The temperature was raised to 85±5°C and the reaction was incubated for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the liquids were separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to yield the intermediate. The intermediate and 1,4-dioxane (8 mL) were transferred to a reaction flask, stirred, and then 2,4-dichloro-5-fluoropyrimidine (281 mg, 1.67 mmol) and potassium phosphate (886.5 mg, 4.18 mmol) were added mmol), stirred, and tetrakis(triphenylphosphine)palladium (161 mg, 0.14 mmol) was added to the reaction flask, and then purified water (2 mL) was added, and the reaction was carried out at 100° C. in a microwave for 1 hour. After the reaction was completed, concentrated, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 157 mg of the title compound as a yellow solid. MS(ESI): 335.1 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ8.55(d, J=3.2Hz, 1H), 7.94(d, J=10.4Hz, 1H), 2.44(s, 3H), 2.21-2.06(m, 6H) ), 1.97-1.88 (m, 2H).

步骤8)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-4'-[D])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺Step 8) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-4'-[D])-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-4'-[D](112mg,0.58mmol)，5-(1-(甲基哌啶-4-基)吡啶-2-胺(63mg,0.19mmol)，Pd ₂(dba) ₃(18mg,0.02mmol),xant-phos(22mg,0.04mmol)以及碳酸铯(184mg,0.57mmol)溶解在1，4-二氧六环(5mL)，然后通氮气，微波100℃反应1小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物89mg为淡黄色固体。MS(ESI):490.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.35(d,J＝8.4Hz,1H),8.24(d,J＝2.0Hz,1H),8.16(s,1H),7.91(d,J＝11.2Hz,1H),7.63(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.13-3.10(m,2H),2.58-2.53(m,1H),2.44(s,3H),2.40(s,3H),2.26-2.08(m,8H),2.03-1.90(m,6H)。 Add 5'-(2-chloro-5-fluoropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-4 to the reaction flask in turn '-[D] (112 mg, 0.58 mmol), 5-(1-(methylpiperidin-4-yl)pyridin-2-amine (63 mg, 0.19 mmol), Pd ₂ (dba) ₃ (18 mg, 0.02 mmol) ), xant-phos (22mg, 0.04mmol) and cesium carbonate (184mg, 0.57mmol) were dissolved in 1,4-dioxane (5mL), and then nitrogen was passed through, and the reaction was carried out at 100°C for 1 hour. The liquid was concentrated, extracted, passed through celite, separated, concentrated, and then separated by TLC and purified by HPLC, and lyophilized to prepare 89 mg of the title compound as a pale yellow solid. MS(ESI): 490.3 [M+H] ⁺ . ¹ H -NMR (400MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 7.91(d, J=11.2Hz, 1H), 7.63(dd, J1 ⁼ 8.8Hz, J2=2.4Hz, 1H), 3.13-3.10(m, 2H), ^2.58-2.53 (m, 1H) ), 2.44(s, 3H), 2.40(s, 3H), 2.26-2.08(m, 8H), 2.03-1.90(m, 6H).

实施例7 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物27) Example 7 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl _- 3,4-[D2])- Nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 27)

步骤1)2-乙酰基-2-(2-丙烯-1-基)-4-戊烯酸乙酯Step 1) Ethyl 2-acetyl-2-(2-propen-1-yl)-4-pentenoate

向反应瓶中依次加入乙酰乙酸乙酯(13.2g,100mmol)、碳酸钾(42g，304mmol)和60mL的DMF。然后向反应瓶中缓慢滴加3-溴丙烯(30g,248mmol)。通氮气保护，加热到85℃反应12小时。将反应液倒入冰水中，用乙酸乙酯萃取，分离，有机相用食盐水洗涤3次(3*100ML)，浓缩，柱层析分离得到标题化合物7g为无水油状物。MS(ESI):211.3[M+H] ⁺。 To the reaction flask were sequentially added ethyl acetoacetate (13.2 g, 100 mmol), potassium carbonate (42 g, 304 mmol) and 60 mL of DMF. Then 3-bromopropene (30 g, 248 mmol) was slowly added dropwise to the reaction flask. Under nitrogen protection, heated to 85°C for 12 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, separated, the organic phase was washed three times with brine (3*100ML), concentrated, and separated by column chromatography to obtain 7 g of the title compound as an anhydrous oil. MS(ESI): 211.3 [M+H] ⁺ .

步骤2)3-(2-丙烯-1-基)-5-己烯-2-酮Step 2) 3-(2-Propen-1-yl)-5-hexen-2-one

将2-乙酰基-2-(2-丙烯-1-基)-4-戊烯酸乙酯(7.0g,35mmol)溶解在20mL的DMF加入到反应瓶中，加入LiCl(2.8g,60mmol)，通氮气后将反应液升温到150℃反应20小时。反应毕，将反应液降温到室温，加入冰水后，萃取，分液，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物2.4g为无色油状物。MS(ESI):139.3[M+H] ⁺。 2-Acetyl-2-(2-propen-1-yl)-4-pentenoic acid ethyl ester (7.0 g, 35 mmol) was dissolved in 20 mL of DMF and added to the reaction flask, and LiCl (2.8 g, 60 mmol) was added. , the reaction solution was heated to 150°C for 20 hours after nitrogen flow. After the reaction was completed, the reaction solution was cooled to room temperature, and ice water was added, followed by extraction, liquid separation, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography to obtain 2.4 g of the title compound as a colorless oil. MS(ESI): 139.3 [M+H] ⁺ .

步骤3)1-(3-环戊烯-1-基)乙酮Step 3) 1-(3-cyclopenten-1-yl)ethanone

向反应瓶中依次加入3-(2-丙烯-1-基)-5-己烯-2-酮(2.4g,17mmol)、Grubbs cat ^1st(720mg,0.87mmol)和20mL的DCM，通氮气室温反应15小时。反应毕，过滤，浓缩，柱层析分离得到标题化合物450mg为无色油状物。MS(ESI):111.3[M+H] ⁺。 3-(2-propen-1-yl)-5-hexen-2-one (2.4 g, 17 mmol), Grubbs cat ^1st (720 mg, 0.87 mmol) and 20 mL of DCM were sequentially added to the reaction flask, and the room temperature was purged with nitrogen. The reaction was carried out for 15 hours. After the reaction was completed, the mixture was filtered, concentrated, and separated by column chromatography to obtain 450 mg of the title compound as a colorless oil. MS(ESI): 111.3 [M+H] ⁺ .

步骤4)1-(环戊基-3，4-[D ₂])乙酮 Step 4) 1-(cyclopentyl _- 3,4-[D2])ethanone

向反应瓶中依次加入1-(3-环戊烯-1-基)乙酮(450mg,4.5mmol)、碳酸铯(70mg,0.21mmol)、钯碳(20mg)和5mL氘代甲醇(CH ₃OD)，然后通入氘气(1atm),加热到40℃反应12小时。反应毕，过滤，浓缩得到标题化合物300mg为黄色油状物。MS(ESI):115.1[M+H] ⁺。 1-(3-cyclopenten-1-yl)ethanone (450 mg, 4.5 mmol), cesium carbonate (70 mg, 0.21 mmol), palladium on carbon (20 mg) and 5 mL of deuterated methanol (CH ₃ ) were added to the reaction flask in sequence OD), then passed deuterium gas (1 atm), heated to 40 ℃ and reacted for 12 hours. The reaction was completed, filtered and concentrated to obtain 300 mg of the title compound as a yellow oil. MS(ESI): 115.1 [M+H] ⁺ .

步骤5)5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-3,4-[D ₂] Step 5) 5'-Bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3' _- indole]-3,4-[D2]

向反应瓶中依次加入4-溴-2-氟苯肼盐酸盐(600mg,2.91mmol)、1-(环戊基-3，4-[D ₂])乙酮(300mg,2.71mmol)和三乙胺(600mg,5.9mmol)以及12mL甲醇。然后保持在35℃反应3小时后，将反应液降温到-10℃后，缓慢滴加浓硫酸(1.2g,12.2mmol)。滴加完，40℃继续反应12小时。反应毕，用氨水调节PH＝8，萃取，浓缩，柱层析分离得到标题化合物130mg为黄色油状物。MS(ESI):284.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ7.24(d,J＝3.6Hz,1H),7.27(d,J＝8.8Hz,1H),2.32(s,3H),2.06-2.01(m,4H)，1.83-1.80(m,2H)。 To the reaction flask were sequentially added 4-bromo-2-fluorophenylhydrazine hydrochloride (600 mg, 2.91 mmol), 1-(cyclopentyl-3,4-[D ₂ ])ethanone (300 mg, 2.71 mmol) and Triethylamine (600 mg, 5.9 mmol) and 12 mL of methanol. Then, after the reaction was kept at 35° C. for 3 hours, the temperature of the reaction solution was lowered to −10° C., and then concentrated sulfuric acid (1.2 g, 12.2 mmol) was slowly added dropwise. After the dropwise addition, the reaction was continued at 40°C for 12 hours. After the reaction was completed, the pH was adjusted to 8 with ammonia water, extracted, concentrated, and separated by column chromatography to obtain 130 mg of the title compound as a yellow oil. MS(ESI): 284.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ7.24(d,J=3.6Hz,1H),7.27(d,J=8.8Hz,1H),2.32(s,3H),2.06-2.01(m,4H) ), 1.83-1.80 (m, 2H).

步骤6)5'-(2-氯-5-氟嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-3,4-[D ₂] Step 6) 5'-(2-Chloro-5-fluoropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-3,4- [ _D2 ]

在氮气保护下，向反应瓶中加入异丙醇(10mL)、5'-溴-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂](130mg,0.46mmol)、醋酸钾(58mg,0.59mmol)和双联频哪醇硼酸酯(152mg,0.59mmol)，搅拌，加入1,1’-二(二苯磷基)二茂铁二氯化钯(134mg,0.18mmol)。升温至85±5℃保温反应12小时。反应液减压浓缩，然后加入纯化水和乙酸乙酯萃取，分液，水相废弃。将得到的有机相过滤并减压浓缩，得到中间体。将中间体和1，4-二氧六环(8mL)转入反应瓶中，搅拌，然后加入2,4-二氯-5-氟嘧啶(106mg,0.63mmol)和磷酸钾(267mg,1.26mmol)，搅拌，向反应瓶中加入四(三苯基膦)钯(48.5mg,0.042mmol)，然后再加入纯化水(2mL)，微波100℃反应1小时。反应毕，浓缩，萃取，分离，无水硫酸钠干燥，过滤，浓缩，柱层析分离得到标题化合物为87mg为黄色固体。MS(ESI):336.1[M+H] ⁺。 Under nitrogen protection, isopropanol (10 mL), 5'-bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'- base-3,4-[D ₂ ] (130 mg, 0.46 mmol), potassium acetate (58 mg, 0.59 mmol) and bispinacol boronate (152 mg, 0.59 mmol), stir, add 1,1'-bis (Diphenylphosphoryl)ferrocene palladium dichloride (134 mg, 0.18 mmol). The temperature was raised to 85±5°C and the reaction was incubated for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the liquids were separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to yield the intermediate. The intermediate and 1,4-dioxane (8 mL) were transferred to a reaction flask, stirred, and then 2,4-dichloro-5-fluoropyrimidine (106 mg, 0.63 mmol) and potassium phosphate (267 mg, 1.26 mmol) were added ), stirred, and tetrakis(triphenylphosphine)palladium (48.5 mg, 0.042 mmol) was added to the reaction flask, and then purified water (2 mL) was added, and the reaction was carried out at 100° C. in a microwave for 1 hour. After the reaction was completed, concentrated, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 87 mg of the title compound as a yellow solid. MS(ESI): 336.1 [M+H] ⁺ .

步骤7)5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺 Step 7) 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl _- 3,4-[D2])- Nitro-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

向反应瓶中依次加入5'-(2-氯-5-氟嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-3,4-[D ₂](70mg,0.208mmol)，5-(1-(甲基哌啶-4-基)吡啶-2-胺(50mg,0.25mmol)，Pd ₂(dba) ₃(19.2mg,0.021mmol),xant-phos(24mg,0.042mmol)以及碳酸铯(202.8mg,0.624mmol)溶解在1，4-二氧六环(8mL)，然后通氮气，微波100℃反应1小时。反应毕，将反应液浓缩，萃取，过硅藻土，分离，继续浓缩，再经过TLC分离和HPLC纯化，冻干制备得到标题化合物25mg为浅黄色固体。MS(ESI):491.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.45(d,J＝3.6Hz,1H),8.35(d,J＝8.4Hz,1H),8.29(s,1H),8.24(d,J＝2.0Hz,1H),7.91(d,J＝0.8Hz,1H),7.88(d,J＝0.8Hz,1H),7.62(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.12-3.09(m,2H),2.59-2.51(m,1H),2.42(s,3H),2.40(s,3H),2.23-2.07(m,7H),1.97-1.88(m,5H)。 Add 5'-(2-chloro-5-fluoropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-3 to the reaction flask , 4-[D ₂ ] (70 mg, 0.208 mmol), 5-(1-(methylpiperidin-4-yl)pyridin-2-amine (50 mg, 0.25 mmol), Pd ₂ (dba) ₃ (19.2 mg , 0.021 mmol), xant-phos (24 mg, 0.042 mmol) and cesium carbonate (202.8 mg, 0.624 mmol) were dissolved in 1,4-dioxane (8 mL), and then nitrogen was passed through, and the reaction was carried out at 100 °C for 1 hour. After completion, the reaction solution was concentrated, extracted, passed through celite, separated, concentrated, and then separated by TLC, purified by HPLC, and lyophilized to prepare 25 mg of the title compound as a pale yellow solid. MS(ESI): 491.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J=3.6 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 8.24 (d, J =2.0Hz,1H),7.91(d,J=0.8Hz,1H),7.88(d,J=0.8Hz,1H),7.62(dd,J ¹ =8.8Hz,J ² =2.4Hz,1H), 3.12-3.09(m,2H), 2.59-2.51(m,1H), 2.42(s,3H), 2.40(s,3H), 2.23-2.07(m,7H), 1.97-1.88(m,5H).

实施例8 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物32) Example 8 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 32)

步骤1)5-氟-4-(7'-氟-2'-(甲基-[D3])螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺Step 1) 5-Fluoro-4-(7'-Fluoro-2'-(methyl-[D3])spiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-( 5-(1-(Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

依次向反应瓶中加入5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基)嘧啶-2-氨基(230mg,0.47mmol)、氘代盐酸(87mg,0.47mmol)和10mL重水。然后加热到95℃反应3小时。反应毕，冷却到室温，并用氘代氢氧化钠调节PH值到8，用DCM进行萃取，浓缩，并用DCM和氘代甲醇重结晶得到标题化合物163mg为淡黄色固体。MS(ESI):492.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.34(d,J＝8.8Hz,1H),8.23(d,J＝2.0Hz,1H),8.14(s,1H),7.98(s,1H),7.91(dd,J ¹＝11.2Hz,J ²＝1.2Hz,1H),7.61(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.04-3.01(m,2H),2.53-2.49(m,1H),2.37(s,3H),2.22-2.07(m,8H),1.91-1.70(m,6H)。 Add 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-( 1-Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amino (230 mg, 0.47 mmol), deuterated hydrochloric acid (87 mg, 0.47 mmol) and 10 mL of deuterated water. Then heated to 95°C for 3 hours. After the reaction was completed, it was cooled to room temperature, adjusted to pH 8 with deuterated sodium hydroxide, extracted with DCM, concentrated, and recrystallized with DCM and deuterated methanol to obtain 163 mg of the title compound as a pale yellow solid. MS(ESI): 492.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.14 ( s, 1H), 7.98 (s, 1H), 7.91 (dd, J ¹ =11.2Hz, J ² =1.2Hz, 1H), 7.61 (dd, J ¹ =8.8Hz, J ² =2.4Hz, 1H), 3.04-3.01 (m, 2H), 2.53-2.49 (m, 1H), 2.37 (s, 3H), 2.22-2.07 (m, 8H), 1.91-1.70 (m, 6H).

实施例9 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基-[D ₃])-哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物2) Example 9 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methyl-[ _D3 ])-piperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 2)

按照实施例1和4相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 1 and 4.

MS(ESI):495.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.05(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),3.34-3.21(m,2H),2.65–2.60(m,1H),2.52–2.50(m,2H),2.40(s,3H),2.24–2.11(m,6H),2.09–1.88(m,6H)。 MS(ESI): 495.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.44(d, J=3.6Hz, 1H), 8.05(s, 1H), 7.98(s, 1H), 7.91(d, J=11.2Hz, 1H), 3.34-3.21(m,2H), 2.65-2.60(m,1H), 2.52-2.50(m,2H), 2.40(s,3H), 2.24-2.11(m,6H), 2.09-1.88(m,6H) ).

实施例10 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基-[D])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物3)Example 10 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methyl-[D])piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 3)

按照实施例1相似的步骤合成得到标题化合物。MS(ESI):490.4[M+H] ⁺。 The title compound was synthesized according to the procedure similar to Example 1. MS(ESI): 490.4 [M+H] ⁺ .

实施例11 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基-[D ₂])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物4) Example 11 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-( Methyl-[D2])piperidin-4-yl)pyridin- ₂ -yl)pyrimidin-2-amine (Compound 4)

按照实施例1相似的步骤合成得到标题化合物。MS(ESI):491.4[M+H] ⁺。 The title compound was synthesized according to the procedure similar to Example 1. MS(ESI): 491.4 [M+H] ⁺ .

实施例12 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-3,4-[D ₂])吡啶-2-基)嘧啶-6-[D]-2-胺(化合物6) Example 12 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -yl)pyrimidin-6-[D]-2-amine (Compound 6)

按照实施例2和3相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 2 and 3.

MS(ESI):492.3[M+H] ⁺。 ¹H-NMR(400MHz,DMSO-d ₆)δ9.99(s,1H),8.19(d,J＝2.4Hz,1H),8.12(d,J＝8.8Hz,1H)，8.01(s,1H),7.84(d,J＝11.6Hz,1H),7.66(dd,J ¹＝8.4Hz,J ²＝2.4Hz,1H),2.88-2.85(m,2H),2.34(s,3H),2.20(s,3H),2.10-2.05(m,6H),2.08-1.96(m,2H),1.75-1.72(m,5H)。 MS(ESI): 492.3 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ9.99(s,1H),8.19(d,J=2.4Hz,1H),8.12(d,J=8.8Hz,1H), 8.01(s,1H) ),7.84(d,J=11.6Hz,1H),7.66(dd,J1 ⁼ 8.4Hz,J2=2.4Hz,1H ⁾ ,2.88-2.85(m,2H),2.34(s,3H),2.20 (s, 3H), 2.10-2.05 (m, 6H), 2.08-1.96 (m, 2H), 1.75-1.72 (m, 5H).

实施例13 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-6-[D]-2-胺(化合物7) Example 13 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-6-[D]-2-amine (Compound 7)

按照实施例2和4相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 2 and 4.

MS(ESI):493.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.01-7.98(m,2H),7.91(d,J＝10.8Hz,1H),3.20-3.17(m,2H),2.62-2.55(m,1H),2.48(s,3H),2.41(s,3H),2.33-2.03(m，8H),2.08-1.86(m，6H)。 MS(ESI): 493.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ8.01-7.98(m, 2H), 7.91(d, J=10.8Hz, 1H), 3.20-3.17(m, 2H), 2.62-2.55(m, 1H) , 2.48(s, 3H), 2.41(s, 3H), 2.33-2.03(m, 8H), 2.08-1.86(m, 6H).

实施例14 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物8) Example 14 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) yl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 8)

按照实施例1和2相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 1 and 2.

MS(ESI):493.2[M+H] ⁺。 ¹H-NMR(400MHz,DMSO-d ₆)δ9.99(s,1H),8.20(d,J＝2.4Hz,1H),8.13(d,J＝8.8Hz,1H),8.01(s,1H),7.85(d,J＝12.0Hz,1H),7.66(dd,J ¹＝8.4Hz,J ²＝2.0Hz,1H),2.89-2.85(m,2H),2.75-2.71(m,1H),2.34(s,3H),2.10-1.96(m,8H),1.76-1.65(m,6H)。 MS(ESI): 493.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ9.99(s, 1H), 8.20(d, J=2.4Hz, 1H), 8.13(d, J=8.8Hz, 1H), 8.01(s, 1H) ), 7.85(d, J=12.0Hz, 1H), 7.66(dd, J1 ⁼ 8.4Hz, J2=2.0Hz, 1H), ^2.89-2.85 (m, 2H), 2.75-2.71(m, 1H) , 2.34(s, 3H), 2.10-1.96(m, 8H), 1.76-1.65(m, 6H).

实施例15 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基-[D ₃])哌啶-4-基-3,4-[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-6-[D]-2-胺(化合物9) Example 15 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) yl-[ _D3 ])piperidin-4-yl-3,4-[D2])pyridin- ₂ -yl-3,4,6-[ _D3 ])pyrimidine-6-[D]-2- Amine (Compound 9)

按照实施例1-4相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedure similar to Example 1-4.

MS(ESI):498.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.02(s,1H),7.98(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝0.8Hz,1H),3.17-3.14(m,2H),2.41(s,3H),2.26-2.08(m,8H),1.97-1.88(m,7H)。 MS(ESI): 498.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.98 (s, 1H), 7.91 (dd, J ¹ =10.8 Hz, J ² =0.8 Hz, 1H), 3.17-3.14 (m , 2H), 2.41 (s, 3H), 2.26-2.08 (m, 8H), 1.97-1.88 (m, 7H).

实施例16 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基-[D ₃])哌啶-4-基-3,4-[D ₂])吡啶-2-基)嘧啶-6-[D]-2-胺(化合物10) Example 16 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) yl-[ _D3 ])piperidin-4-yl-3,4-[D2])pyridin- ₂ -yl)pyrimidin-6-[D]-2-amine (Compound 10)

按照实施例1-3相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedure similar to Example 1-3.

MS(ESI):495.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ9.99(s,1H),8.19(d,J＝2.4Hz,1H),8.12(d,J＝8.8Hz,1H)，8.01(s,1H),7.84(d,J＝11.6Hz,1H),7.65(dd,J ¹＝8.4Hz,J ²＝2.4Hz,1H),2.89-2.86(m,2H),2.34(s,3H),2.08-2.05(m,6H),2.01-1.96(m,2H),1.75-1.72(m,5H)。 MS(ESI): 495.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 9.99(s, 1H), 8.19(d, J=2.4Hz, 1H), 8.12(d, J=8.8Hz, 1H), 8.01(s, 1H), 7.84(d,J=11.6Hz,1H),7.65(dd,J1 ⁼ 8.4Hz,J2=2.4Hz,1H), ^2.89-2.86 (m,2H),2.34(s,3H),2.08-2.05 (m, 6H), 2.01-1.96 (m, 2H), 1.75-1.72 (m, 5H).

实施例17 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-3,4-[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-6-[D]-2-胺(化合物11) Example 17 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -yl-3,4,6-[ _D3 ])pyrimidin-6-[D]-2-amine (Compound 11)

按照实施例2-4相似的步骤合成得到标题化合物。The title compound was synthesized according to the similar procedure of Example 2-4.

MS(ESI):495.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ7.98(s,1H),7.95(s,1H),7.91(d,J＝10.8Hz,1H),3.15-3.12(m,2H),2.45(s,3H),2.41(s,3H),2.23- 2.09(m,7H),1.91-1.88(m,6H)。 MS(ESI): 495.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ7.98(s,1H),7.95(s,1H),7.91(d,J=10.8Hz,1H),3.15-3.12(m,2H),2.45(s , 3H), 2.41 (s, 3H), 2.23-2.09 (m, 7H), 1.91-1.88 (m, 6H).

实施例18 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基-[D ₃])哌啶-4-基)吡啶-2-基-3,4-[D ₂]-6-[D])嘧啶-6-[D]-2-胺(化合物12) Example 18 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) [ _D3 ])piperidin-4-yl)pyridin- ₂ -yl-3,4-[D2]-6-[D])pyrimidin-6-[D]-2-amine (Compound 12)

按照实施例1、2和4相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 2 and 4.

MS(ESI):496.0[M+H] ⁺。 ¹H-NMR(400MHz,DMSO-d ₆)δ10.00(s,1H),8.18(s,1H),8.01(s,1H),7.84(d,J＝11.6Hz,1H),2.91-2.88(m,2H),2.34(s,3H),2.10-1.99(m,9H),1.77-1.65(m,6H)。 MS(ESI): 496.0 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.00(s, 1H), 8.18(s, 1H), 8.01(s, 1H), 7.84(d, J=11.6Hz, 1H), 2.91-2.88 (m, 2H), 2.34 (s, 3H), 2.10-1.99 (m, 9H), 1.77-1.65 (m, 6H).

实施例19 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基-[D ₃])哌啶-4-基-3,4-[D ₂])吡啶-2-基)嘧啶-2-胺(化合物14) Example 19 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) yl-[ _D3 ])piperidin-4-yl-3,4-[D2])pyridin- ₂ -yl)pyrimidin-2-amine (Compound 14)

按照实施例1和3相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 1 and 3.

MS(ESI):494.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.51(brs,1H),8.46(d,J＝3.6Hz,1H),8.35(d,J＝8.8Hz,1H),8.26(d,J＝2.0Hz,1H),7.97(s,1H),7.90(d,J＝11.2Hz,1H),7.61(dd,J ¹＝8.4Hz,J ²＝2.0Hz,1H),3.09-3.07(m,2H),2.40(s,3H),2.18-2.08(m,8H),1.90-1.87(m,5H)。 MS(ESI): 494.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.51 (brs, 1H), 8.46 (d, J=3.6 Hz, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.26 (d, J=2.0 Hz,1H),7.97(s,1H),7.90(d,J=11.2Hz,1H),7.61(dd,J1 ⁼ 8.4Hz,J2=2.0Hz,1H),3.09-3.07(m,2H ⁾ ), 2.40(s, 3H), 2.18-2.08(m, 8H), 1.90-1.87(m, 5H).

实施例20 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-3,4-[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物15) Example 20 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 15)

按照实施例3和4相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 3 and 4.

MS(ESI):494.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),7.98(s,1H),7.95(s,1H),7.91(d,J＝10.8Hz,1H),3.23-3.21(m,2H),2.51(s,3H),2.41(s,3H),2.33-2.20(m,2H),2.19-1.82(m,11H)。 MS(ESI): 494.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ8.43(d, J=3.6Hz, 1H), 7.98(s, 1H), 7.95(s, 1H), 7.91(d, J=10.8Hz, 1H), 3.23-3.21(m,2H), 2.51(s,3H), 2.41(s,3H), 2.33-2.20(m,2H), 2.19-1.82(m,11H).

实施例21 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基-[D ₃])哌啶-4-基-3,4-[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物16) Example 21 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) yl-[ _D3 ])piperidin-4-yl-3,4-[D2])pyridin- ₂ -yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 16)

按照实施例1、3和4相似的步骤合成得到标题化合物。The title compound was synthesized following similar procedures in Examples 1, 3 and 4.

MS(ESI):497.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),7.98(s,1H),7.95(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝1.2Hz,1H),3.17-3.15(m,2H),2.41(s,3H),2.27-2.19(m,2H),2.16-1.87(m,11H)。 MS(ESI): 497.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=3.6 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.91 (dd, J ¹ =10.8 Hz, J ² = 1.2Hz, 1H), 3.17-3.15 (m, 2H), 2.41 (s, 3H), 2.27-2.19 (m, 2H), 2.16-1.87 (m, 11H).

实施例22 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-2,2,6,6-[D ₄])吡啶-2-基)嘧啶-2-胺(化合物17) Example 22 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin- ₄ -yl-2,2,6,6-[D4])pyridin-2-yl)pyrimidin-2-amine (Compound 17)

按照实施例3相似的步骤合成得到标题化合物。MS(ESI):493.3[M+H] ⁺。 The title compound was synthesized according to the procedure similar to Example 3. MS(ESI): 493.3 [M+H] ⁺ .

实施例23 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-4-[D])吡啶-2-基)嘧啶-2-胺(化合物18)Example 23 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-4-[D])pyridin-2-yl)pyrimidin-2-amine (Compound 18)

按照实施例3相似的步骤合成得到标题化合物。MS(ESI):490.3[M+H] ⁺。 The title compound was synthesized according to the procedure similar to Example 3. MS(ESI): 490.3 [M+H] ⁺ .

实施例24 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-甲基哌啶-4-基-2,2,3,3,4,5,5,6,6-[D ₉])吡啶-2-基)嘧啶-2-胺(化合物19) Example 24 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methyl) ylpiperidin-4-yl-2,2,3,3,4,5,5,6,6-[ _D9 ])pyridin-2-yl)pyrimidin-2-amine (Compound 19)

按照实施例3相似的步骤合成得到标题化合物。MS(ESI):498.2[M+H] ⁺。 The title compound was synthesized according to the procedure similar to Example 3. MS(ESI): 498.2 [M+H] ⁺ .

实施例25 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物22) Example 25 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-6'-[D])-nitrogen- (5-(1-(Methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 22)

按照实施例1和5相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 1 and 5.

MS(ESI):493.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),8.36(d,J＝8.8Hz,1H),8.21(d,J＝2.4Hz,1H),8.02(s,1H),7.98(s,1H),7.65(d,J＝8.8Hz,1H),3.28-3.27(m,2H),2.62-2.53(m,3H),2.40(s,3H),2.26-1.90(m,8H),1.88-1.72(m,4H)。 MS(ESI): 493.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=3.6 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.02 ( s,1H),7.98(s,1H),7.65(d,J=8.8Hz,1H),3.28-3.27(m,2H),2.62-2.53(m,3H),2.40(s,3H),2.26 -1.90(m, 8H), 1.88-1.72(m, 4H).

实施例26 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物23)Example 26 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl-6'-[D])-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 23)

按照实施例2和5相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 2 and 5.

MS(ESI):491.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.34(d,J＝8.4Hz,1H),8.24(s,1H),8.23(d,J＝8.0Hz,1H),7.98(s,1H),7.61(dd,J ¹＝8.4Hz,J ²＝2.4Hz,1H),3.08-3.05(m,2H),2.53-2.50(m,1H),2.40(s,3H),2.39(s,3H),2.22- 2.08(m,8H),1.91-1.84(m,6H)。 MS(ESI): 491.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.34(d, J=8.4Hz, 1H), 8.24(s, 1H), 8.23(d, J=8.0Hz, 1H), 7.98(s, 1H), 7.61(dd, J ¹ =8.4Hz, J ² =2.4Hz, 1H), 3.08-3.05(m, 2H), 2.53-2.50(m, 1H), 2.40(s, 3H), 2.39(s, 3H) , 2.22- 2.08 (m, 8H), 1.91-1.84 (m, 6H).

实施例27 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物24) Example 27 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl-6'-[D])-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 24)

按照实施例4和5相似的步骤合成得到标题化合物。The title compound was synthesized following similar procedures in Examples 4 and 5.

MS(ESI):493.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.01(s,1H),7.98(s,1H),3.14-3.11(m,2H),2.57-2.53(m,1H),2.44(s,3H),2.40(s,3H),2.24-2.07(m,8H),1.96-1.88(m,6H)。 MS(ESI): 493.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.44(d, J=3.6Hz, 1H), 8.01(s, 1H), 7.98(s, 1H), 3.14-3.11(m, 2H), 2.57-2.53 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.24-2.07 (m, 8H), 1.96-1.88 (m, 6H).

实施例28 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-4',6'-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物26) Example 28 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl-4', ₆ '-[D2] )-nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 26)

按照实施例6相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Example 6.

MS(ESI):491.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),8.32(d,J＝8.4Hz,1H),8.24(d,J＝2.4Hz,1H),8.15(s,1H),7.60(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.21-3.17(m,2H),2.58-2.53(m,1H),2.48(s,3H),2.43(s,3H),2.29-2.01(m,8H),1.98-1.86(m,6H)。 MS(ESI): 491.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.43 (d, J=3.6 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.15 ( s, 1H), 7.60(dd, J ¹ =8.8Hz, J ² =2.4Hz, 1H), 3.21-3.17(m, 2H), 2.58-2.53(m, 1H), 2.48(s, 3H), 2.43 (s, 3H), 2.29-2.01 (m, 8H), 1.98-1.86 (m, 6H).

实施例29 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物28) Example 29 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl _- 3,4-[D2])- Nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 28)

按照实施例4和7相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 4 and 7.

MS(ESI):494.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.40(d,J＝3.6Hz,1H),8.10(s,1H),7.98(s,1H),7.91(d,J＝10.8Hz,1H),3.17-3.14(m,2H),2.57-2.56(m,1H),2.46(s,3H),2.40(s,3H),2.29-2.00(m,7H),1.97-1.88(m,5H)。 MS(ESI): 494.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.40(d, J=3.6Hz, 1H), 8.10(s, 1H), 7.98(s, 1H), 7.91(d, J=10.8Hz, 1H), 3.17-3.14(m,2H), 2.57-2.56(m,1H), 2.46(s,3H), 2.40(s,3H), 2.29-2.00(m,7H), 1.97-1.88(m,5H).

实施例30 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物29) Example 30 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl _- 3,4-[D2])- Nitrogen-(5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 29)

按照实施例1和7相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 1 and 7.

MS(ESI):494.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.36(d,J＝8.8Hz,1H),8.22(d,J＝2.0Hz,1H),8.06(s,1H),7.98(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝1.2Hz,1H),7.66(dd,J ¹＝8.8Hz,J ²＝2.0Hz,1H),3.27-3.26(m,2H),2.63-2.60(m,1H),2.40(s,3H),2.19-2.07(m,7H),1.97-1.86(m,5H)。 MS(ESI): 494.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.06 ( s,1H),7.98(s,1H),7.91(dd,J1 ⁼ ^10.8Hz ,J2=1.2Hz,1H),7.66(dd,J1 ⁼ 8.8Hz,J2=2.0Hz,1H ⁾ , 3.27-3.26(m, 2H), 2.63-2.60(m, 1H), 2.40(s, 3H), 2.19-2.07(m, 7H), 1.97-1.86(m, 5H).

实施例31 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物30) Example 31 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl _- 3,4-[D2])- Nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 30)

按照实施例2和7相似的步骤合成得到标题化合物。The title compound was synthesized following the procedures similar to Examples 2 and 7.

MS(ESI):492.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.34(d,J＝3.6Hz,1H),8.22(d,J＝2.0Hz,1H),8.14(s,1H),7.98(s,1H),7.91(d,J＝10.8Hz,1H),7.63(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.20-3.17(m,2H),2.62-2.54(m,1H),2.47(s,3H),2.40(s,3H),2.30-2.01(m,7H),1.98-1.86(m,5H)。 MS(ESI): 492.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.34(d, J=3.6Hz, 1H), 8.22(d, J=2.0Hz, 1H), 8.14(s, 1H), 7.98(s, 1H), 7.91(d,J=10.8Hz,1H),7.63(dd,J1 ⁼ 8.8Hz,J2=2.4Hz,1H ⁾ ,3.20-3.17(m,2H),2.62-2.54(m,1H),2.47 (s, 3H), 2.40 (s, 3H), 2.30-2.01 (m, 7H), 1.98-1.86 (m, 5H).

实施例32 5-氟-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基-3,4-[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物31) Example 32 5-Fluoro-4-(7'-Fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl _- 3,4-[D2])- Nitrogen-(5-(1-(methylpiperidin-4-yl-3,4-[D2])pyridin- ₂ -yl-3,4,6-[ _D3 ])pyrimidin-2-amine ( Compound 31)

按照实施例1、3、4和7相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 3, 4 and 7.

MS(ESI):499.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.06(s,1H),7.98(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝1.2Hz,1H),3.28-3.25(m,2H),2.40(s,3H),2.19-2.09(m,6H),1.96-1.86(m,5H)。 MS(ESI): 499.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.91 (dd, J ¹ =10.8 Hz, J ² =1.2Hz, 1H), 3.28-3.25(m, 2H), 2.40(s, 3H), 2.19-2.09(m, 6H), 1.96-1.86(m, 5H).

实施例33 5-氟-4-(7'-氟-2'-(甲基-D ₃)螺[环戊烷-1,3'-吲哚]-5'-基-2,2,3,3,4,4,5,5-[D ₈])-氮-(5-(1-(甲基哌啶-4-基)-吡啶-2-基)嘧啶-2-胺(化合物33) Example 33 5-Fluoro-4-(7'-fluoro-2'-(methyl- _D3 )spiro[cyclopentane-1,3'-indol]-5'-yl-2,2,3 , _3,4,4,5,5- [D8])-nitrogen-(5-(1-(methylpiperidin-4-yl)-pyridin-2-yl)pyrimidin-2-amine (Compound 33 )

按照实施例7和8相似的步骤合成得到标题化合物。MS(ESI):500.3[M+H] ⁺。 The title compound was synthesized following a procedure similar to that of Examples 7 and 8. MS(ESI): 500.3 [M+H] ⁺ .

实施例34 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物34) Example 34 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 34)

按照实施例2和8相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 2 and 8.

MS(ESI):493.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.34(d,J＝8.8Hz,1H),8.24(s,1H),8.23(s,1H),7.98(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝0.8Hz,1H),7.61(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.05-3.02(m,2H),2.54-2.50(m,1H),2.38(s,3H),2.22-2.08(m,8H),1.91-1.83(m,6H)。 MS(ESI): 493.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.34(d, J=8.8Hz, 1H), 8.24(s, 1H), 8.23(s, 1H), 7.98(s, 1H), 7.91(dd, J ¹ =10.8Hz, J2= ^0.8Hz , 1H), 7.61 (dd, J1 ⁼ 8.8Hz, J2=2.4Hz, 1H ⁾ , 3.05-3.02 (m, 2H), 2.54-2.50 (m, 1H) , 2.38(s, 3H), 2.22-2.08(m, 8H), 1.91-1.83(m, 6H).

实施例35 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5- (1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物35) Example 35 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen- (5-(1-(Methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 35)

按照实施例1和8相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 1 and 8.

MS(ESI):495.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.34(d,J＝8.4Hz,1H),8.23(d,J＝2.4Hz,1H),8.13(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),7.62(dd,J ¹＝8.4Hz,J ²＝2.0Hz,1H),3.07-3.04(m,2H),2.57-2.51(m,1H),2.20-2.08(m,8H),1.91-1.88(m,6H)。 MS(ESI): 495.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.13 ( s,1H),7.98(s,1H),7.91(d,J=11.2Hz,1H),7.62(dd,J1 ⁼ 8.4Hz,J2=2.0Hz,1H), ^3.07-3.04 (m,2H) ), 2.57-2.51(m, 1H), 2.20-2.08(m, 8H), 1.91-1.88(m, 6H).

实施例36 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物36) Example 36 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen- (5-(1-(Methylpiperidin-4-yl)pyridin-2-yl-3,4,6-[ _D3 ])pyrimidin-2-amine (Compound 36)

按照实施例4和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 4 and 8.

MS(ESI):495.1[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.45(d,J＝3.6Hz,1H),8.43(s,1H),7.98(s,1H),7.91(dd,J ¹＝11.2Hz,J ²＝1.2Hz,1H),3.04-3.01(m,2H),2.53-2.49(m,1H),2.37(s,1H),2.21-2.08(m,8H),1.91-1.82(m,6H)。 MS(ESI): 495.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J=3.6 Hz, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.91 (dd, J ¹ =11.2 Hz, J ² = 1.2Hz, 1H), 3.04-3.01 (m, 2H), 2.53-2.49 (m, 1H), 2.37 (s, 1H), 2.21-2.08 (m, 8H), 1.91-1.82 (m, 6H).

实施例37 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物37) Example 37 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-6'- [D])-Nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 37)

按照实施例5和8相似的步骤合成得到标题化合物。The title compound was synthesized according to the procedures similar to Examples 5 and 8.

MS(ESI):493.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝4.0Hz,1H),8.34(d,J＝8.4Hz,1H),8.23(d,J＝2.0Hz,1H),8.13(s,1H),7.98(s,1H),7.62 (dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.08-3.05(m,2H),2.55-2.49(m,1H),2.40(s,3H),2.20-2.07(m,8H),1.91-1.88(m,6H)。 MS(ESI): 493.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=4.0 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.13 ( s, 1H), 7.98(s, 1H), 7.62 (dd, J ¹ =8.8Hz, J ² =2.4Hz, 1H), 3.08-3.05(m, 2H), 2.55-2.49(m, 1H), 2.40 (s, 3H), 2.20-2.07 (m, 8H), 1.91-1.88 (m, 6H).

实施例38 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-6'-[D])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物38) Example 38 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-6'- [D])-Nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 38)

按照实施例4、5和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 4, 5 and 8.

MS(ESI):494.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ12.87(brs,1H),8.65(d,J＝8.8Hz,1H),8.23(s,1H),8.02(s,1H),8.00(s,1H),3.68-3.65(m,2H),2.98-2.92(m,3H),2.87(s,3H),2.75-2.66(m,2H),2.40-1.89(m,10H)。 MS(ESI): 494.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ12.87(brs,1H),8.65(d,J=8.8Hz,1H),8.23(s,1H),8.02(s,1H),8.00(s,1H ), 3.68-3.65(m, 2H), 2.98-2.92(m, 3H), 2.87(s, 3H), 2.75-2.66(m, 2H), 2.40-1.89(m, 10H).

实施例39 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基)-氮-(5-(1-(甲基-[D ₃])哌啶-4-基-3,4-[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物39) Example 39 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen- (5-(1-(Methyl-[ _D3 ])piperidin-4-yl-3,4-[D2])pyridin- ₂ -yl-3,4,6-[ _D3 ])pyrimidine- 2-amine (compound 39)

按照实施例1、3、4和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 3, 4 and 8.

MS(ESI):500.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.06(s,1H),7.98(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝1.2Hz,1H),3.17-3.15(m,2H),2.30-2.20(m,1H),2.19-2.03(m,8H),1.93-1.87(m,4H)。 MS(ESI): 500.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J=3.6 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.91 (dd, J ¹ =10.8 Hz, J ² = 1.2Hz, 1H), 3.17-3.15 (m, 2H), 2.30-2.20 (m, 1H), 2.19-2.03 (m, 8H), 1.93-1.87 (m, 4H).

实施例40 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物40) Example 40 5-Fluoro-4-(7'-Fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-3,4 -[D2])-nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin- ₂ -yl)pyrimidin-2-amine (Compound 40)

按照实施例7和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 7 and 8.

MS(ESI):494.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.44(d,J＝3.6Hz,1H),8.34(d,J＝8.4Hz,1H),8.23(s,1H),8.21(s,1H),8.14(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),7.62(dd,J ¹＝8.4Hz,J ²＝2.0Hz,1H),3.08-3.05(m,2H),2.55-2.51(m,1H),2.40(s,3H),2.18-2.07(m,6H),1.91-1.89(m,6H)。 MS(ESI): 494.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ8.44(d,J=3.6Hz,1H),8.34(d,J=8.4Hz,1H),8.23(s,1H),8.21(s,1H), 8.14(s,1H),7.98(s,1H),7.91(d,J=11.2Hz,1H),7.62(dd,J1 ⁼ 8.4Hz,J2=2.0Hz,1H ⁾ ,3.08-3.05(m , 2H), 2.55-2.51(m, 1H), 2.40(s, 3H), 2.18-2.07(m, 6H), 1.91-1.89(m, 6H).

实施例41 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基-3,4--[D ₂])吡啶-2-基-3,4,6-[D ₃])嘧啶-2-胺(化合物41) Example 41 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-3,4 _- [D2])-nitrogen-(5-(1-(methyl-[ _D3 ])piperidin-4-yl-3,4--[D2])pyridin- ₂ -yl-3,4 ,6-[D ₃ ])pyrimidin-2-amine (Compound 41)

按照实施例1、3、4、7和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 3, 4, 7 and 8.

MS(ESI):502.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),8.07(s,1H),7.98(s,1H),7.91(dd,J ¹＝10.8Hz,J ²＝2.8Hz,1H),3.06-3.03(m,2H),2.20-2.07(m,6H),1.91-1.86(m,5H)。 MS(ESI): 502.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=3.6 Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.91 (dd, J ¹ =10.8 Hz, J ² = 2.8Hz, 1H), 3.06-3.03 (m, 2H), 2.20-2.07 (m, 6H), 1.91-1.86 (m, 5H).

实施例42 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物42) Example 42 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-3,4 _- [D2])-nitrogen-(5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 42)

按照实施例1、7和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 7 and 8.

MS(ESI):497.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),8.34(d,J＝7.6Hz,1H),8.21(d,J＝2.4Hz,1H),8.02(s,1H),7.98(s,1H),7.91(dd,J ¹＝11.2Hz,J ²＝1.6Hz,1H),7.63(dd,J ¹＝8.4Hz,J ²＝2.4Hz,1H),3.09-3.07(m,2H),2.54-2.51(m,1H),2.18-2.07(m,6H),1.89-1.88(m,6H)。 MS(ESI): 497.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=3.6 Hz, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.02 ( s,1H),7.98(s,1H),7.91(dd,J1 ⁼ ^11.2Hz ,J2=1.6Hz,1H),7.63(dd,J1 ⁼ 8.4Hz,J2=2.4Hz,1H ⁾ , 3.09-3.07(m, 2H), 2.54-2.51(m, 1H), 2.18-2.07(m, 6H), 1.89-1.88(m, 6H).

实施例43 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物43) Example 43 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-3,4 -[D2])-nitrogen-(5-(1-(methylpiperidin-4-yl)pyridin- ₂ -yl)pyrimidin-6-[D]-2-amine (Compound 43)

按照实施例2、7和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 2, 7 and 8.

MS(ESI):495.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.37(d,J＝8.8Hz,1H),8.23(d,J＝2.0Hz,1H),8.07(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),7.66(d,J＝8.4Hz,1H),3.33-3.31(m,2H),2.62(s,3H),2.52-2.49(m,2H),2.27-2.07(m,7H),1.99-1.87(m,4H)。 MS(ESI): 495.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 8.37(d, J=8.8Hz, 1H), 8.23(d, J=2.0Hz, 1H), 8.07(s, 1H), 7.98(s, 1H), 7.91(d,J＝11.2Hz,1H),7.66(d,J＝8.4Hz,1H),3.33-3.31(m,2H),2.62(s,3H),2.52-2.49(m,2H),2.27 -2.07(m, 7H), 1.99-1.87(m, 4H).

实施例44 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-3,4-[D ₂])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物44) Example 44 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-3,4 _- [D2])-nitrogen-(5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (compound 44)

按照实施例1、2、7和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 2, 7 and 8.

MS(ESI):498.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.39(d,J＝8.8Hz,1H),8.22(d,J＝3.6Hz,1H),8.05(s,1H),7.98(s,1H),7.91(dd,J ¹＝11.2Hz,J ²＝0.8Hz,1H),7.70(d,J＝8.4Hz,1H),3.59-3.54(m,2H),2.84-2.75(m,3H),2.55-2.40(m,2H),2.55-2.40(m,2H),2.22-1.87(m,5H)。 MS(ESI): 498.3 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ )δ8.39(d,J=8.8Hz,1H),8.22(d,J=3.6Hz,1H),8.05(s,1H),7.98(s,1H), 7.91(dd,J1 ⁼ 11.2Hz,J2= ^0.8Hz ,1H),7.70(d,J=8.4Hz,1H),3.59-3.54(m,2H),2.84-2.75(m,3H),2.55 -2.40(m, 2H), 2.55-2.40(m, 2H), 2.22-1.87(m, 5H).

实施例45 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-4'-[D])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-2-胺(化合物45) Example 45 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-4'- [D])-Nitrogen-(5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Compound 45)

按照实施例1、6和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 6 and 8.

MS(ESI):496.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.43(d,J＝3.6Hz,1H),8.34(d,J＝8.8Hz,1H),8.22(d,J＝2.4Hz,1H),8.10(s,1H),7.91(d,J＝11.2Hz,1H),7.62(dd,J ¹＝8.8Hz,J ²＝2.4Hz,1H),3.05-3.02(m,2H),2.54-2.48(m,1H),2.20-2.09(m,8H),1.91-1.80(m,6H)。 MS(ESI): 496.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=3.6 Hz, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 8.10 ( s,1H),7.91(d,J=11.2Hz,1H),7.62(dd,J1 ⁼ 8.8Hz,J2=2.4Hz,1H),3.05-3.02(m,2H), ^2.54-2.48 (m , 1H), 2.20-2.09 (m, 8H), 1.91-1.80 (m, 6H).

实施例46 5-氟-4-(7'-氟-2'-(甲基-[D ₃])螺[环戊烷-1,3'-吲哚]-5'-基-4'-[D])-氮-(5-(1-(甲基-[D ₃])哌啶-4-基)吡啶-2-基)嘧啶-6-[D]-2-胺(化合物46) Example 46 5-Fluoro-4-(7'-fluoro-2'-(methyl-[ _D3 ])spiro[cyclopentane-1,3'-indole]-5'-yl-4'- [D])-Nitrogen-(5-(1-(methyl-[ _D3 ])piperidin-4-yl)pyridin-2-yl)pyrimidin-6-[D]-2-amine (Compound 46)

按照实施例1、2、6和8相似的步骤合成得到标题化合物。The title compound was synthesized following a procedure similar to that of Examples 1, 2, 6 and 8.

MS(ESI):497.3[M+H] ⁺。 ¹H-NMR(400MHz,CDCl ₃)δ8.34(d,J＝8.8Hz,1H),8.22(d,J＝2.0Hz,1H),8.14(s,1H),7.91(d,J＝10.8Hz,1H),7.62(dd,J ¹＝8.4Hz,J ²＝2.4Hz,1H),3.06-3.03(m,2H),2.53-2.43(m,1H),2.18-2.08(m,8H),1.90-1.87(m,6H)。 MS(ESI): 497.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=8.8 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J=10.8 Hz,1H),7.62(dd,J1 ⁼ 8.4Hz,J2=2.4Hz,1H),3.06-3.03(m,2H),2.53-2.43(m,1H), ^2.18-2.08 (m,8H) ,1.90-1.87(m,6H).

以下通过试验例的方式来说明本发明的有益效果。The beneficial effects of the present invention are described below by means of test examples.

试验例1:本发明的化合物对人脑胶质瘤U87MG细胞的增殖抑制测定Test Example 1: Assay for Inhibitory Proliferation of Human Glioma U87MG Cells by Compounds of the Present Invention

1.1实验材料1.1 Experimental materials

人脑胶质瘤细胞U87MG购于南京科佰生物科技有限公司；对照化合物1，参考专利WO2017/092635A1中的制备方法制备；细胞检测设备为In Cell Analyzer 2200(GE Healthcare)；实验用到的试剂或耗材如下表所示：Human brain glioma cell U87MG was purchased from Nanjing Kebai Biotechnology Co., Ltd.; the control compound 1 was prepared by referring to the preparation method in the patent WO2017/092635A1; the cell detection equipment was In Cell Analyzer 2200 (GE Healthcare); the reagents used in the experiment or consumables as shown in the table below:

表1Table 1

试剂或耗材Reagents or consumables	货号article number	厂家factory
DMSODMSO	D2650D2650	SigmaSigma
PBSPBS	20012-1720012-17	GibcoGibco
DAPIDAPI	D8417D8417	SigmaSigma
甲醛formaldehyde	4760847608	SigmaSigma
Triton ^TM X-100 Triton ^TM X-100	T9284T9284	SigmaSigma
MEMMEM	12561-05612561-056	GibcoGibco

MEM NEAAMEM NEAA	20797052079705	GibcoGibco
丙酮酸钠Sodium pyruvate	11140-05011140-050	GibcoGibco
FBSFBS	1009914110099141	GibcoGibco
青霉素/链霉素Penicillin/Streptomycin	1514012215140122	Thermo FisherThermo Fisher
96孔黑色透明底细胞板96-well black clear bottom cell plate	36033603	CorningCorning

1.2实验准备1.2 Experiment preparation

1.2.1 U87 MG培养基的配制:MEM(低糖)+10％FBS+1％青霉素/链霉素+1％丙酮酸钠+1％MEM NEAA1.2.1 Preparation of U87 MG medium: MEM (low glucose) + 10% FBS + 1% penicillin/streptomycin + 1% sodium pyruvate + 1% MEM NEAA

1.2.2对照化合物1和供试化合物溶液的配制：1.2.2 Preparation of control compound 1 and test compound solutions:

(1)配制对照化合物1溶液(1) Preparation of control compound 1 solution

a.取15μL的1.25mM的对照化合物1溶液加到96孔板的B1孔中，在B2-B11每孔中加入20μL DMSO，从B1孔中取5μL溶液加到B2孔中，混匀，依次稀释到B11，得到依次3倍稀释的对照化合物1溶液；a. Add 15 μL of 1.25mM control compound 1 solution to well B1 of 96-well plate, add 20 μL DMSO to each well of B2-B11, add 5 μL solution from well B1 to well B2, mix well, and then Dilute to B11 to obtain a 3-fold dilution of the control compound 1 solution;

b.在96孔板C2-C11中加入95.2μL的培养基，取B2-B11稀释溶液4.8μL加到C2-C11中，(孔C1浓度60μM)，混匀。b. Add 95.2 μL of culture medium to C2-C11 of 96-well plate, add 4.8 μL of B2-B11 dilution solution to C2-C11, (well C1 concentration 60 μM), mix well.

(2)配制供试化合物溶液(2) Preparation of test compound solution

a.分别取15μL的1.25mM的供试化合物溶液加到96孔板D1孔中，在D2-D11每孔中加入20μL DMSO，从D1孔中取5μL溶液加到D2孔中混匀，依次稀释到D11，得到依次3倍稀释的供试化合物溶液；a. Add 15μL of 1.25mM test compound solution to well D1 of 96-well plate, add 20μL DMSO to each well of D2-D11, add 5μL solution from D1 well to D2 well, mix well, and dilute sequentially To D11, obtain the test compound solution diluted 3 times successively;

b.在96孔板E2-E11中加入95.2μL的培养基，取D2-D11稀释溶液4.8μL加到E2-E11中，(孔E1浓度60μM)，混匀。b. Add 95.2 μL of culture medium to 96-well plate E2-E11, add 4.8 μL of D2-D11 dilution solution to E2-E11, (well E1 concentration 60 μM), mix well.

1.3实验过程1.3 Experimental process

1.3.1 U87 MG细胞分别以4000cells/100μL/well接种至96孔黑色透明底细胞板，37℃培养过夜；1.3.1 U87 MG cells were seeded into 96-well black clear bottom cell plates at 4000 cells/100 μL/well, and cultured at 37°C overnight;

1.3.2将上述稀释好的对照化合物1溶液和供试化合物溶液分别以20μL/孔加入至接种有细胞的培养板中，37℃孵育72h；1.3.2 Add 20 μL/well of the above-diluted control compound 1 solution and test compound solution to the culture plate inoculated with cells, and incubate at 37°C for 72h;

1.3.3固定：取出96孔板，去除培养基，于室温下每孔加入50μL中性甲醛固定液(甲醛：PBS＝1:9),室温避光固定10-30min；1.3.3 Fixation: Take out the 96-well plate, remove the medium, add 50 μL of neutral formaldehyde fixative solution (formaldehyde:PBS=1:9) to each well at room temperature, and fix it in the dark for 10-30min at room temperature;

1.3.4 1×PBS(50μL/well)洗涤2次；1.3.4 Wash twice with 1×PBS (50μL/well);

1.3.5透化处理：0.2％Triton ^TM X-100(50μL/well)透化处理5-10min； 1.3.5 Permeabilization: 0.2% Triton ^™ X-100 (50μL/well) for 5-10min;

1.3.6 1×PBS(50μL/well)洗涤2次；1.3.6 Wash twice with 1×PBS (50μL/well);

1.3.7染色：DAPI(50μL/well)染色(PBS:DAPI＝5000:1)，室温避光孵育20min；1.3.7 Staining: DAPI (50μL/well) staining (PBS:DAPI=5000:1), incubated at room temperature for 20min in the dark;

1.3.8 1×PBS(50μL/well)洗涤3次，加入PBS(100μL/well)；1.3.8 Wash 3 times with 1×PBS (50 μL/well), add PBS (100 μL/well);

1.3.9 In Cell Analyzer扫描，分析每孔细胞数目；1.3.9 In Cell Analyzer scan, analyze the number of cells per well;

1.3.10数据处理：1.3.10 Data processing:

按如下公式计算各化合物在各浓度点的抑制率，并通过软件Graphpad Prism 6.0进行曲线拟合得到IC ₅₀值。 The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC ₅₀ value was obtained by curve fitting with the software Graphpad Prism 6.0.

1.4实验结果1.4 Experimental results

表2受试化合物对U87MG细胞的抑制活性检测结果Table 2 Test results of the inhibitory activity of test compounds on U87MG cells

化合物编号Compound number	IC ₅₀值(nM) _IC50 value (nM)
对照化合物1Control compound 1	9.359.35
11	11.3611.36
22	1.611.61
55	3.803.80
66	6.236.23
77	15.2415.24
88	5.745.74
99	5.745.74
1010	9.459.45
1111	6.166.16
1212	2.412.41
1313	4.944.94
1414	2.372.37
1515	11.6211.62
1616	5.755.75
2020	1.611.61
21twenty one	3.253.25

22twenty two	5.745.74
23twenty three	0.650.65
24twenty four	2.992.99
2525	1.471.47
2727	7.517.51
2828	6.316.31
2929	5.265.26
3030	3.133.13
3131	3.113.11
3232	5.215.21
3434	3.813.81
3535	5.415.41
3636	10.2410.24
3737	6.856.85
3838	4.224.22
3939	3.943.94
4040	1.331.33
4141	3.393.39
4242	2.582.58
4343	2.772.77
4444	1.291.29
4545	2.792.79
4646	2.082.08

从表2数据可以看出，氘代后的供试化合物与未氘代的对照化合物相比，对U87MG细胞的抑制活性相近，以上实验结果证明：本发明的化合物相对于对照化合物1进行氘代修饰后，保持了药物的细胞学活性。As can be seen from the data in Table 2, the deuterated test compound has similar inhibitory activity on U87MG cells compared with the non-deuterated control compound. After modification, the cytological activity of the drug was maintained.

试验例2本发明化合物在人肝微粒体中的稳定性Test Example 2 Stability of the compounds of the present invention in human liver microsomes

2.1实验材料2.1 Experimental materials

人肝微粒体购买于Corning，储存于-80℃冰箱；还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)购于Chem-impex international；对照化合物1，参考专利WO2017/092635A1中的制备方法制备；对照品为睾酮、双氯芬酸和普罗帕酮。Human liver microsomes were purchased from Corning and stored in -80°C refrigerator; reduced nicotinamide adenine dinucleotide phosphate (NADPH) was purchased from Chem-impex international; reference compound 1 was prepared by referring to the preparation method in patent WO2017/092635A1 ; Control substances are testosterone, diclofenac and propafenone.

2.2实验条件2.2 Experimental conditions

-测试浓度：1μM(DMSO 0.01％)；- Test concentration: 1 μM (DMSO 0.01%);

-缓冲液：100mM磷酸盐缓冲液，pH7.4；- Buffer: 100 mM phosphate buffer, pH 7.4;

-微粒体蛋白浓度：0.5mg/ml；- Microsomal protein concentration: 0.5 mg/ml;

-辅因子：NADPH和MgCl ₂； - cofactors: NADPH and MgCl ₂ ;

-NADPH浓度：1nM。-NADPH concentration: 1 nM.

2.3实验步骤2.3 Experimental steps

2.3.1准备8块96孔孵育板，分别命名为T0、T5、T10、T20、T30、T60、Blank60和NCF60。前6块孵育板对应的反应时间点分别为0、5、10、20、30和60分钟。Blank 60板中不加入供试品、对照化合物1或对照品并在孵育60分钟后取样。NCF60板中用磷酸钾盐缓冲液代替NADPH工作液进行孵育60分钟。2.3.1 Prepare eight 96-well incubation plates, named T0, T5, T10, T20, T30, T60, Blank60 and NCF60, respectively. The reaction time points corresponding to the first 6 incubation plates were 0, 5, 10, 20, 30 and 60 minutes, respectively. Blank 60 plates were blanked with no test article, control compound 1, or controls and samples were taken after 60 minutes of incubation. Incubate for 60 min in NCF60 plates with potassium phosphate buffer instead of NADPH working solution.

2.3.2在T0、T5、T10、T20、T30、T60和NCF60板上分别加入5μL供试品、对照化合物1或对照品工作液和445μL微粒体工作液，在Blank60板中只添加微粒体工作液，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。2.3.2 Add 5 μL of the test article, reference compound 1 or reference substance working solution and 445 μL of microsome working solution to T0, T5, T10, T20, T30, T60 and NCF60 plates respectively, and add only microsome working solution to Blank60 plate The above-mentioned incubation plate was then placed in a 37°C water bath for pre-incubation for about 10 minutes.

2.3.3预孵育结束后，除NCF60板和T0板外，每个样品孔内添加44μL NADPH工作液以启动反应，在NCF60板上每孔添加50μL磷酸钾盐缓冲液。2.3.3 After the pre-incubation, in addition to the NCF60 plate and the T0 plate, add 44 μL of NADPH working solution to each sample well to start the reaction, and add 50 μL of potassium phosphate buffer to each well on the NCF60 plate.

2.3.4孵育适当时间(5、10、20、30和60分钟)后，分别在每个样品孔中加入180μL终止液(含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的乙腈溶液)以终止反应。2.3.4 After an appropriate incubation time (5, 10, 20, 30 and 60 minutes), add 180 μL of stop solution (acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol) to each sample well, respectively. solution) to stop the reaction.

2.3.5 T0板的制备：在T0板中先加入180μL终止液(含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的乙腈溶液)，然后再加入6μL NADPH工作液。2.3.5 Preparation of T0 plate: First add 180 μL of stop solution (acetonitrile solution containing 200 ng/mL tolbutamide and 200 ng/mL labetalol) to the T0 plate, and then add 6 μL of NADPH working solution.

2.3.6所有样品板摇匀并在4000rpm离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于LC-MS/MS进行分析。2.3.6 All sample plates were shaken and centrifuged at 4000 rpm for 20 minutes, and then 80 μL of supernatant was taken from each well and diluted into 240 μL of pure water for LC-MS/MS analysis.

2.3.7数据分析：2.3.7 Data Analysis:

供试品、对照化合物1和对照品在样品中的浓度均采用液相色谱-串联质谱(LC-MS/MS)方法进行测定。斜率值(Ke)通过样品的剩余百分比与孵育时间曲线的自然对数的线性回归来确定。体外半衰期(体外T _1/2)由斜率值确定： The concentrations of the test substance, reference compound 1 and reference substance in the samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Slope values (Ke) were determined by linear regression of the percent remaining of the sample versus the natural logarithm of the incubation time curve. The in vitro half-life (in vitro T _1/2 ) is determined from the slope value:

2.4本发明化合物在人肝微粒体中的代谢稳定性实验结果2.4 Experimental results of metabolic stability of the compounds of the present invention in human liver microsomes

测试对照化合物1的半衰期(T _1/2)的平均值为23.9分钟；在同一批次检测样品中，将测试化合物的半衰期比对照化合物1短1.4分钟-10分钟的定义为C，将测试化合物的半衰期与对照化合物1相差正负1分钟以内的定义为B，将测试化合物的半衰期比对照化合物1长1.4分钟-10分钟的定义为A，将测试化合物的半衰期比对照化合物1长15分钟-30分钟的定义为A ⁺。 The average value of the half-life (T _1/2 ) of the test control compound 1 was 23.9 minutes; in the same batch of test samples, the half-life of the test compound was 1.4-10 minutes shorter than that of the control compound 1 as C, and the test compound was defined as C. The half-life of the test compound 1.4 minutes-10 minutes longer than that of the control compound 1 is defined as B, and the half-life of the test compound is 15 minutes longer than that of the control compound 1- 30 minutes is defined as A ⁺ .

表3受试化合物在人肝微粒体中的代谢稳定性检测结果Table 3 Metabolic stability test results of test compounds in human liver microsomes

化合物编号Compound number	半衰期(T _1/2) Half-life (T _1/2 )
对照化合物1Control compound 1	23.9分钟23.9 minutes
11	AA
22	AA
77	CC
99	AA
1010	CC
1212	AA
1313	AA
1414	AA
1515	AA
2020	BB
21twenty one	AA
22twenty two	AA
24twenty four	AA
2525	AA
2727	AA

2828	AA
2929	AA
3030	AA
3131	AA
3232	AA
3434	BB
3535	A ⁺ A ⁺
3636	AA
3737	AA
3838	AA
3939	AA
4040	AA
4141	AA
4242	AA
4343	AA
4444	AA

从表3数据可以看出，化合物1、2、9、12-15、21、22、24、25、27-32、35-44在人肝微粒体中代谢稳定性均优于对照化合物1，尤其是化合物35，其在人肝微粒体半衰期比对照化合物1长15-30分钟，其在人肝微粒体中的代谢稳定性比对照化合物1有了显著的提高，说明了本发明中的部分化合物具有更长的作用时间，可能具有更好的临床应用价值。From the data in Table 3, it can be seen that the metabolic stability of compounds 1, 2, 9, 12-15, 21, 22, 24, 25, 27-32 and 35-44 in human liver microsomes is better than that of the control compound 1, Especially compound 35, its half-life in human liver microsomes is 15-30 minutes longer than that of control compound 1, and its metabolic stability in human liver microsomes is significantly improved than that of control compound 1, which explains part of the present invention. Compounds with longer duration of action may have better clinical application value.

而化合物7、10作为对照化合物的半衰期却低于对照化合物1，说明氘代对化合物的代谢性质的影响是不可预测的，某些位点的氘代非但不能延长半衰期，反而可能会缩短半衰期，劣化其药代动力学性质。However, the half-lives of compounds 7 and 10 as reference compounds were lower than that of reference compound 1, indicating that the effect of deuterium on the metabolic properties of the compounds is unpredictable. Deuterium at some sites can not prolong the half-life, but may shorten the half-life. Deteriorates its pharmacokinetic properties.

本发明已经通过上述实施例进行了说明，但应当理解的是，上述实施例只是用于举例和说明的目的，而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是，本发明并不局限于上述实施例，根据本发明的教导还可以做出更多种的变型和修改，这些变型和修改均落在本发明所要求保护的范围以内。本发明的保护范围由附属的权利要求书及其等效范围所界定。The present invention has been described by the above-mentioned embodiments, but it should be understood that the above-mentioned embodiments are only for the purpose of illustration and description, and are not intended to limit the present invention to the scope of the described embodiments. In addition, those skilled in the art can understand that the present invention is not limited to the above-mentioned embodiments, and more variations and modifications can also be made according to the teachings of the present invention, and these variations and modifications all fall within the protection claimed in the present invention. within the range. The protection scope of the present invention is defined by the appended claims and their equivalents.

Claims

式(I)所示的化合物或其药学上可接受的盐：The compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

其中，R ¹-R ²⁹分别是H或D，且R ¹-R ²⁹中至少一个是D；和 wherein R ¹ -R ²⁹ are each H or D, and at least one of R ¹ -R ²⁹ is D; and

所述式(I)化合物不包括以下化合物：The compounds of formula (I) do not include the following compounds:
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R ¹-R ¹⁵、和R ¹⁷-R ²⁹中至少一个是D； The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ -R ¹⁵ and R ¹⁷ -R ²⁹ is D;

优选地，R ¹-R ¹⁵、R ¹⁷、和R ¹⁹-R ²⁹中至少一个是D； Preferably, at least one of R ¹ -R ¹⁵ , R ¹⁷ , and R ¹⁹ -R ²⁹ is D;

优选地，R ¹-R ¹²、R ¹⁷、R ¹⁹-R ²⁹中至少一个是D； Preferably, at least one of R ¹ -R ¹² , R ¹⁷ , R ¹⁹ -R ²⁹ is D;

优选地，R ¹-R ³、R ⁸-R ⁹、R ¹⁷、R ²¹、R ²³、R ²⁷-R ²⁹中至少一个是D。 Preferably, at least one of R ¹ -R ³ , R ⁸ -R ⁹ , R ¹⁷ , R ²¹ , R ²³ , R ²⁷ -R ²⁹ is D.
根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that,

R ¹-R ³是D；和/或 R ¹ -R ³ are D; and/or

R ⁸和R ⁹是D；和/或 ^R8 and ^R9 are D; and/or

R ¹³-R ¹⁵是D；和/或 R ¹³ - R ¹⁵ are D; and/or

R ¹⁶是D；和/或 R ¹⁶ is D; and/or

R ¹⁷是D；和/或 R ¹⁷ is D; and/or

R ¹⁸是D；和/或 R ¹⁸ is D; and/or

R ²¹和R ²³是D；和/或 R ²¹ and R ²³ are D; and/or

R ²⁷-R ²⁹是D。 R ²⁷ -R ²⁹ are D.
根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that,

R ¹-R ³是D；和/或 R ¹ -R ³ are D; and/or

R ⁸和R ⁹是D；和/或 ^R8 and ^R9 are D; and/or

R ¹³-R ¹⁵是D；和/或 R ¹³ - R ¹⁵ are D; and/or

R ¹⁷是D；和/或 R ¹⁷ is D; and/or

R ²¹和R ²³是D；和/或 R ²¹ and R ²³ are D; and/or

R ²⁷-R ²⁹是D。 R ²⁷ -R ²⁹ are D.
根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that,

R ¹-R ³是D；和/或 R ¹ -R ³ are D; and/or

R ⁸-R ⁹是D；和/或 ^R8 - ^R9 are D; and/or

R ¹⁷是D；和/或 R ¹⁷ is D; and/or

R ²¹和R ²³是D；和/或 R ²¹ and R ²³ are D; and/or

R ²⁷-R ²⁹是D。 R ²⁷ -R ²⁹ are D.
根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐，其特征在于，R ¹⁶是H，或R ¹³-R ¹⁵是H，或R ¹⁸是H。 The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R ¹⁶ is H, or R ¹³ -R ¹⁵ are H, or R ¹⁸ is H.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，当R ¹⁶是D时， The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein when R ¹⁶ is D,

R ¹-R ³是D，和R ¹³-R ¹⁵是D；和/或 R ¹ -R ³ are D, and R ¹³ -R ¹⁵ are D; and/or

R ¹-R ³是D，R ⁸-R ⁹是D，和R ¹³-R ¹⁵是D；和/或 R ¹ -R ³ are D, R ⁸ -R ⁹ are D, and R ¹³ -R ¹⁵ are D; and/or

R ²¹和R ²³是D；和/或 R ²¹ and R ²³ are D; and/or

R ²⁷-R ²⁹是D；和/或 R ²⁷ - R ²⁹ are D; and/or

R ¹⁷是D和R ²⁷-R ²⁹是D；和/或 ^R17 is D and ^R27 - ^R29 is D; and/or

R ²¹是D，R ²³是D，和R ²⁷-R ²⁹是D；和/或 R ²¹ is D, R ²³ is D, and R ²⁷ - R ²⁹ are D; and/or

R ¹-R ³是D，R ²¹是D，R ²³是D，和R ²⁷-R ²⁹是D。 R ¹ -R ³ are D, R ²¹ is D, R ²³ is D, and R ²⁷ -R ²⁹ are D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有式(II)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II):

其中R ¹、R ²、R ³中至少一个是D，R ¹³-R ¹⁵分别是H或D； wherein at least one of R ¹ , R ² and R ³ is D, and R ¹³ -R ¹⁵ are H or D respectively;

优选地，R ¹、R ²、和R ³是D,R ¹³-R ¹⁵分别是H或D； Preferably, R ¹ , R ² , and R ³ are D, and R ¹³ -R ¹⁵ are H or D, respectively;

更优选，R ¹、R ²、和R ³是D,R ¹³-R ¹⁵至少一个是D。 More preferably, R ¹ , R ² , and R ³ are D, and at least one of R ¹³ -R ¹⁵ is D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有式(III)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (III):

其中，R ¹-R ³、R ⁸-R ⁹、R ¹³-R ¹⁵分别是H或D； Wherein, R ¹ -R ³ , R ⁸ -R ⁹ , R ¹³ -R ¹⁵ are H or D respectively;

优选地，R ¹-R ³是D、和/或R ⁸-R ⁹是D、和/或R ¹³-R ¹⁵是D； Preferably, R ¹ -R ³ are D, and/or R ⁸ -R ⁹ are D, and/or R ¹³ -R ¹⁵ are D;

优选地，R ¹-R ³是D、和R ¹³-R ¹⁵是D； Preferably, R ¹ -R ³ are D, and R ¹³ -R ¹⁵ are D;

优选地，R ¹-R ³是D，R ⁸-R ⁹是D，和R ¹³-R ¹⁵是D。 Preferably, R ¹ -R ³ are D, R ⁸ -R ⁹ are D, and R ¹³ -R ¹⁵ are D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有式(IV)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (IV):

其中，R ¹-R ¹⁵中至少一个是D； wherein at least one of R ¹ -R ¹⁵ is D;

优选，R ¹-R ³是D，和/或R ⁸-R ⁹是D。 Preferably, R ¹ -R ³ are D, and/or R ⁸ -R ⁹ are D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有式(V)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (V):

其中，R ¹-R ³、R ¹³-R ¹⁶分别是H或D； wherein, R ¹ -R ³ , R ¹³ -R ¹⁶ are H or D respectively;

优选，R ¹-R ³是D，和/或R ¹³-R ¹⁵是D。 Preferably, R ¹ -R ³ are D, and/or R ¹³ -R ¹⁵ are D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有式(VI)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (VI):

其中，R ¹-R ³、R ⁸、R ⁹、R ¹³-R ¹⁶分别是H或D； Wherein, R ¹ -R ³ , R ⁸ , R ⁹ , R ¹³ -R ¹⁶ are H or D respectively;

优选地，R ¹-R ³是D，和/或R ¹³-R ¹⁵是D，和/或R ⁸和R ⁹是D； Preferably, R ¹ -R ³ are D, and/or R ¹³ -R ¹⁵ are D, and/or R ⁸ and R ⁹ are D;

优选地，R ¹⁶是D。 Preferably, R ¹⁶ is D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有式(VII)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (VII):

其中，R ¹-R ³、R ⁸、R ⁹、和R ¹³-R ²⁶分别是H或D。 wherein R ¹ -R ³ , R ⁸ , R ⁹ , and R ¹³ -R ²⁶ are H or D, respectively.
根据权利要求13所述的化合物或其药学上可接受的盐，其特征在于，The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein

R ¹-R ³是D；和/或 R ¹ -R ³ are D; and/or

R ⁸和R ⁹是D；和/或 ^R8 and ^R9 are D; and/or

R ¹³-R ¹⁵是D；和/或 R ¹³ - R ¹⁵ are D; and/or

R ¹⁶是D；和/或 R ¹⁶ is D; and/or

R ¹⁷是D；和/或 R ¹⁷ is D; and/or

R ²¹和R ²³是D。 R ²¹ and R ²³ are D.
根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物选自：The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
药物组合物，其包含权利要求1-15中任一项所述的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的载体或赋形剂。A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
一种治疗CDK4/6介导的障碍或疾病的方法，包括对有需要的受试者给予有效量的权利要求1-15中任一项所述的化合物或其药学上可接受的盐，或权利要求16所述的药物组合物。A method of treating a CDK4/6-mediated disorder or disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, or The pharmaceutical composition of claim 16.
权利要求1-15中任一项所述的化合物或其药学上可接受的盐，或权利要求16所述的药物组合物在制备用于治疗CDK4/6介导的障碍或疾病的药物中的用途。Use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16 in the manufacture of a medicament for the treatment of a CDK4/6 mediated disorder or disease use.
权利要求1-15中任一项所述的化合物或其药学上可接受的盐，其用于治疗CDK4/6介导的障碍或疾病。The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CDK4/6 mediated disorder or disease.
制备式(VII)化合物的方法，包括下述步骤：在酸存在的条件下，使式(VIII)化合物与氘代试剂反应得到式(VII)化合物The method for preparing the compound of formula (VII) comprises the following steps: in the presence of an acid, the compound of formula (VIII) is reacted with a deuterated reagent to obtain the compound of formula (VII)

其中，R ¹-R ³、R ⁸、R ⁹、R ¹³-R ²⁶分别是H或D； Wherein, R ¹ -R ³ , R ⁸ , R ⁹ , R ¹³ -R ²⁶ are H or D respectively;

优选地，所述酸选自氘代盐酸、盐酸、三氯化铁、三氯化铝、氯化锌、醋酸、醋酸酐、三氟乙酸、三氟乙酸酐、三氟甲烷磺酸、苯甲酸、对甲基苯甲酸、对硝基苯甲酸、对甲氧基苯甲酸、3，5-二硝基苯甲酸、二苯基磷酸、苯基次膦酸、磷酸、次磷酸、苯乙酸、苯丙酸、三甲基乙酸、苯磺酸、对甲苯磺酸、苦杏仁酸、和水杨酸中的至少一种；和/或所述氘代试剂选自d ₆-DMSO、d ₇-DMF、d ₆-丙酮、CD ₃OD、D ₂O、CD ₃CN、和C ₆D ₆中的至少一种； Preferably, the acid is selected from deuterated hydrochloric acid, hydrochloric acid, ferric chloride, aluminum trichloride, zinc chloride, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, benzoic acid , p-Toluic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 3,5-dinitrobenzoic acid, diphenylphosphoric acid, phenylphosphinic acid, phosphoric acid, hypophosphorous acid, phenylacetic acid, benzene at least one of propionic acid, trimethylacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, mandelic acid, and salicylic acid; and/or the deuterated reagent is selected from d ₆ -DMSO, d ₇ -DMF , at least one of d ₆ -acetone, CD ₃ OD, D ₂ O, CD ₃ CN, and C ₆ D ₆ ;

更优选地，所述酸为氘代盐酸，和/或所述氘代试剂为D ₂O。 More preferably, the acid is deuterated hydrochloric acid, and/or the deuterated reagent is D ₂ O.
根据权利要求20所述的方法，其中：The method of claim 20, wherein:

R ¹-R ³是D；和/或 R ¹ -R ³ are D; and/or

R ⁸和R ⁹是D；和/或 ^R8 and ^R9 are D; and/or

R ¹³-R ¹⁵是D；和/或 R ¹³ - R ¹⁵ are D; and/or

R ¹⁶是D；和/或 R ¹⁶ is D; and/or

R ¹⁷是D；和/或 R ¹⁷ is D; and/or

R ²¹和R ²³是D。 R ²¹ and R ²³ are D.
一种式(IX)所示的化合物或其药学上可接受的盐，A compound of formula (IX) or a pharmaceutically acceptable salt thereof,

其中，R ¹⁸-R ²⁹分别是H或D，优选R ¹⁸-R ²⁹分别如权利要求3-7、和13-14任一项中所定义；X为离去基团或氨基； wherein, R ¹⁸ -R ²⁹ are respectively H or D, preferably R ¹⁸ -R ²⁹ are as defined in any one of claims 3-7 and 13-14 respectively; X is a leaving group or an amino group;

优选的，X是卤素或氨基，更优选是氟、溴、氯或氨基。Preferably, X is halogen or amino, more preferably fluorine, bromine, chlorine or amino.
一种制备式(I)化合物的方法，包括使式(IX)化合物转化为式(I)化合物：A method of preparing a compound of formula (I) comprising converting a compound of formula (IX) to a compound of formula (I):

其中：in:

R ¹⁷为D；和 ^R17 is D; and

R ¹-R ¹⁶和R ¹⁸-R ²⁹分别是H或D，优选，R ¹-R ¹⁶和R ¹⁸-R ²⁹分别如权利要求3-5、和7任一项中所定义，优选，R ¹-R ³是D、和/或R ¹³-R ¹⁵是D、和/或R ¹⁶是D、和/或R ¹⁸-R ²⁹是氢。 R ¹ -R ¹⁶ and R ¹⁸ -R ²⁹ are each H or D, preferably, R ¹ -R ¹⁶ and R ¹⁸ -R ²⁹ are as defined in any one of claims 3-5, and 7, respectively, preferably, R ¹ - ^R3 are D, and/or ^R13 - ^R15 are D, and/or ^R16 are D, and/or ^R18 - ^R29 are hydrogen.
一种制备式(IX)化合物的方法，包括下述步骤：在酸存在的条件下，使式(X)化合物或其盐与式(XI)化合物反应得到式(IX)化合物：A method for preparing a compound of formula (IX), comprising the steps of: reacting a compound of formula (X) or a salt thereof with a compound of formula (XI) in the presence of an acid to obtain a compound of formula (IX):

其中，R ¹⁸-R ²⁹分别是H或D，优选R ¹⁸-R ²⁹分别如权利要求3-7、和13-14任一项中所定义，优选R ¹⁸-R ²⁹是氢；X为离去基团或氨基；优选的，X是卤素或氨基，更优选是氟、溴、氯或氨基；和/或 Wherein, R ¹⁸ -R ²⁹ are respectively H or D, preferably R ¹⁸ -R ²⁹ are as defined in any one of claims 3-7 and 13-14, preferably R ¹⁸ -R ²⁹ are hydrogen; X is an isolating Degroup or amino; preferably, X is halogen or amino, more preferably fluorine, bromine, chlorine or amino; and/or

式(X)化合物的盐选自盐酸盐、硫酸盐、甲磺酸盐和对甲苯磺酸盐，优选是盐酸盐。The salt of the compound of formula (X) is selected from the group consisting of hydrochloride, sulfate, mesylate and p-toluenesulfonate, preferably the hydrochloride.
根据权利要求24所述的方法，所述酸为有机酸、无机酸、或路易斯酸；优选所述酸为硫酸、盐酸、磷酸、甲磺酸、对甲苯磺酸、醋酸、ZnCl ₂、FeCl ₃、AlCl ₃或SnCl ₄；优选地，所述酸为硫酸。 The method according to claim 24, wherein the acid is an organic acid, an inorganic acid, or a Lewis acid; preferably, the acid is sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, ZnCl ₂ , FeCl ₃ , AlCl ₃ or SnCl ₄ ; preferably, the acid is sulfuric acid.
根据权利要求25所述的方法，进一步包括下述步骤：The method of claim 25, further comprising the steps of:

(1)使
与氘代试剂反应得到
(1) make
Reaction with deuterated reagents to obtain

(2)使
转化为
或其盐。 (2) make
transform into
or its salt.
根据权利要求26所述的方法，其中所述步骤(1)在Ir(OMe)(cod) ₂存在下进行；和所述氘代试剂选自d ₆-DMSO、d ₇-DMF、d ₆-丙酮、CD ₃OD、D ₂O、CD ₃CN、和C ₆D ₆中的至少一种；优选地，所述氘代试剂为D ₂O。 The method of claim 26, wherein the step ( ₁ ) is carried out in the presence of Ir(OMe)(cod); and the deuterated reagent is selected from the group consisting of d ₆ -DMSO, d ₇ -DMF, d ₆ - At least one of acetone, CD ₃ OD, D ₂ O, CD ₃ CN, and C ₆ D ₆ ; preferably, the deuterated reagent is D ₂ O.